MX2010008420A - Extended release hydrocodone acetaminophen and related methods and uses thereof. - Google Patents

Abstract

The present invention generally provides a method of treatment and improvement of quality of life for patients adversely affected by various pain conditions. One preferred embodiment provides a method of treatment of acute pain, moderate to moderately severe pain, chronic pain, non-cancer pain, osteoarthritic pain, bunionectomy pain or lower back pain in a patient in need thereof, comprising providing at least one or two dosage form having about 15 mg of hydrocodone and its salt and about 500 mg of acetaminophen, once, twice or thrice daily. Preferably, the dosage form is about 30 mg of hydrocodone and about 1000 mg of acetaminophen taken twice daily. Alternatively, the dosage form is about 15 mg of hydrocodone and about 500 mg of acetaminophen taken twice daily.

Description

H IDROCODOIMA ACETAM EXTENDED RELEASE INOFF AND RELATED ETHODS AND THEIR U SOS BACKGROUND A patient's quality of life is adversely affected by pain. In addition, this quality of life is associated with a loss of work productivity, which impacts both the patient and his boss, adversely.

Thus, for example, the moderate to severe pain and physical disability that are symptoms of osteoarthritis (OA) can profoundly affect many aspects of patients' quality of life, including activities of daily living (ADLs). In addition, in other pain conditions such as, lower back pain (LBP), the total cost in loss of productivity in the E L). TO . exceeds $ 100 billion / year. Among the active workers of the US UA. , pain conditions such as LBP, cost the heads approximately $ 61.2 billion / year in lost productive time.

Generally, pain is treated with NSAI Ds or combination optoids to provide effective analgesia in patients with moderate to severe chronic osteoarthritis (OA) pain when less potent treatments are not effective or tolerable, or are contraindicated. Currently, combination opioids are available only in immediate release formulations.

However, these combinations may not adequately address various quality of life problems. Therefore, an improvement in quality of life is desirable through new formulations, which also reduce the loss of productivity, thereby positively impacting both the patient and his / her bosses.

BRIEF DESCRIPTION OF THE PREFERRED MODALITIES The present invention generally provides a method of treatment and improvement of quality of life for patients adversely affected by various pain conditions. A preferred embodiment provides a method of treating acute pain, moderate to moderately severe pain, chronic pain, non-cancer pain, osteoarthritic pain, bunionectomy pain or low back pain in a patient with the need thereof, which comprises providing the less one or two dosage forms having about 15 mg of hydrocodone and its salt and about 500 mg of acetaminophen, once, twice or three times a day. Preferably, the dosage form is about 30 mg of hydrocodone and about 1000 mg of acetaminophen taken twice a day. Alternatively, the two-s form is about 15 mg of hydrocodone and about 500 mg of acetaminophen taken twice a day. Also, preferably, this dosage form can be taken by the patient with or without food. In another aspect of the invention, the co-administration of approximately 240 ml of 40%, 20%, 4% and 0% of etariol in the individual dose form affects the concentration level Jn the average maximum plasma Cmax by < 25% for both hydrocodone and acetaminophen in the patient. In another aspect, the Cma) and the AUC of hydrocodone for a patient with mild to moderately impaired hepatic function is substantially similar to the normal patient and the Cmax and AUC of acetaminophen for a patient with slightly damaged liver function is substantially similar. to the normal patient. Also, no statistically significant differences in effectiveness are observed for the patient metabolizing hydrocodone when the patient is a deficient or competent metabolizer of Cytochrome P450 2 D6 polymorphism.

Another embodiment of the invention provides a method for improving the quality of life in a patient with the need thereof, which comprises administering to the patient a dosage form twice a day of controlled release that includes acetaminophen and hydrocodone or a therapeutically salt effective of them. In yet another embodiment, the invention provides a method for reducing the loss of productivity in a patient having a pain-related condition, which comprises administering to the patient a twice-daily dose-controlled release form that includes acetaminophen and hydrocodone or a therapeutically effective salt thereof. Preferably, the dosage form comprises about 15 mg of hydrocodone or a therapeutically acceptable salt thereof and about 500 mg of acetaminophen. Or preferably, in all the above embodiments, the dosage form comprises about 15 mg of hydrocodone or a therapeutically acceptable salt thereof and about 500 mg of acetaminophen. Alternatively, the dosage form comprises about 30 mg of hydrocodone or a therapeutically acceptable salt thereof and about 1000 mg of acetaminophen.

These and other objectives will be highlighted through the detailed description of the preferred modalities. The compendium should not be considered to limit the scope of the invention.

DESCRIPTION OF THE FIGURES Figure 1 provides response relationships to the exposure of Vicodin CR in acute pain Figure 2 provides average plasma concentration of Hydrocodone and Acetaminophen for 12 hours after the individual dose of 1, 2 and 3 tablet (s) of Vicodin CR (15 mg of hydrocodone bitartrate / 500 mg of Acetaminophen).

Figure 3 provides average plasma concentration of Steady-state Hydrocodone and Acetaminophen After administration of 2 Vicodin CR Tablets (15 mg hydrocodone bitartrate / 500 mg Acetaminophen) Twice a day and 1 Immediate Rse Tablet (10 mg hydrocodone bitartrate / 325 mg Acetaminophen) every 4 hours.

Figure 4 provides an average change in the assessment of VAS marks of CLBP intensity of the subject from the Base Line with double blind to the final evaluation in the CLBP study (Double Blind Maintenance Period; of Efficacy) 'Statistically significant difference (p <0.05) against placebo using an ANCOVA model with factors for the treatment center and study with VAS pain score of baseline double-blind as a covariate.

Figure 5 provides a proportion of patients who achieve various levels of pain reduction from the baseline of the open label to the final evaluation for the VAS intensity assessment of the patient's CLBP (Sustainability period efficacy evaluable data set). DB). Note: P-value = 0.001 for 2 tablets of Vicodin CR against placebo and p-value - 0.049 for 1 tablet of Vicodin CR against placebo for difference test in distribution between treatment groups using the exact Kolmogorov-Smirnov test Mount Cario.

Figure 6 provides a proportion of subjects achieving various levels of pain reduction from the baseline to the maintenance visit of week 12 for the assessment of intensive arthritis pain of the subject by VAS in OA pain study chronicle. Note: The p-value = 0.055 for the difference test in the distribution between treatment groups using the exact Kolmogorov-Smirnov test from Monte Cario.

Figure 7 provides total pain reduction during 12 hours; SPI D VAS Marks Average (0-12 Hours) after the Initial Study Drug Dose that uses LOC F in Acute Pain Study (ITT Data Set). 'Statistically significant difference (p <0.05) against placebo, using an ANCO VA model with factors for treatment, study center, and baseline VAS pain intensity mark as a covariate. † Statistically significant difference (p = 0.05) against 1 Vicodin CR tablet, using an ANCOVA model with factors for treatment, study center, and baseline VAS pain intensity marker as a covariate.

Figure 8 provides the study design for the Example VI I.

Figure 9 provides labor productivity and physical disability (evaluable efficacy data set).

Figure 10 provides the study design for the Hub [mplo] VI I I.

Figure 1 1 provides brief pain inventory (BPI) (evaluable efficacy data set).

Figure 12 provides SF-36 health status survey results (evaluable efficacy data set).

Figure 13 provides the study design for the! Example IX.

Figure 14 provides average reductions: in the assessment of the patient's pain intensity mark from the baseline - average values reported ± SEM (evaluable efficacy data set).

Figure 1 5 provides the study design for Example l X. Figure 16 provides SPI D score score (VAS), for | 0-12 hours.

Figure 17 provides the study design for the Hub [mplo] XVI.

Figure 18 provides average reductions in the assessment of the pain intensity score of the patient from the Ibas e line (Observed cases: Evaluable Efficacy Set) DETAILED DESCRIPTION OF THE PREFERRED MODALITIES Vicodin CR is indicated for the relief of moderate to moderately severe pain. It is administered orally and can be taken with or without food. Vicodin CR should be swallowed completely, and should not be chewed, divided, compressed or dissolved. The recommended dose for adults is two tablets twice a day (approximately every 12 hours), not to exceed 4 tablets in 24 hours. As with other opioid drug products, it is critical to initiate the dosing regimen for each patient individually, taking into account the analgesic treatment before opioid and without the patient's opioid. Attention must be paid to 1 . the general condition and the medical condition of the patient; 2. the daily dose, strength, and type of analgesic (s) the patient has been taking; 3. Opioid exposure and patient's opioid tolerance (if any); Y 4. the balance between pain control and adverse experiences Care should be taken when using low initial doses of Vicodin CR in patients who are not yet opioid tolerant, especially those who receive concurrent treatment with muscle relaxants, sedatives, other active medications CNS. The tolerance of Vicodin CR can be improved to start therapy with a tablet once or twice a day before increasing to two tablets twice a day Patients with acute pain can start with two tablets twice a day if necessary. The maximum dose of Vicodin C R evaluated in controlled studies was 2 tablets twice a day. It is recommended that patients who do not have satisfactory pain relief with two tablets twice a day be re-evaluated.

When treating pain, it is vital to assess the patient regularly and systematically. The therapist should also be regularly reviewed and adjusted based on the patient's own reports of pain and side effects and the clinical judgment of a health professional. When the patient no longer requires therapy with Vicodin CR, the doses should be gradually decreased to prevent signs and symptoms of withdrawal in the physically dependent patient.

Vicodin CR contains 15 mg of hydrocodone bitartrate and 500 mg of acetaminophen. Vicodin CR contains hydrocodone, an opioid with a disadvantage of abuse and is a controlled substance of Schedule II I. Vicodin CR and other opioids used in analgesia, has the potential to abuse them and are sought by drug abusers and people with addiction disorders and are subject to criminal deviation.

Studies of chronic pain Two blind, placebo-controlled, 17-week clinical trials were conducted; a study in patients with chronic low back pain (C LBP) and a study in patients with osteoarthritis (OA) pain. In the CLBP study, patients were enrolled in a 3 week open label titration period (where all patients had up to 2 tablets of Vicodin CR twice a day), which was then followed by a double treatment period. randomized 12-week-old randomized trial where patients received 1 tablet of Vicodin CR twice daily, 2 tablets of Vicodin CR twice daily, or placebo. In the OA study, patients were randomly selected for 2 tablets of Vicodin CR twice daily or placebo, initially, in a three-week titration period.; which was then followed by the maintenance period of 12 weeks. Both studies had a one-week reduction period together with a one-week follow-up period for a total duration of 17 weeks. The adverse reactions arising from the treatment reported in = 5% of patients during the CLBP and OA studies were presented in Tables 1 and 2 below. Adverse reactions that occurred at a rate less than or equal to placebo were not included in the tables below in this section.

Table 1. Adverse reactions emerging from treatment reported in 5% of patients during the open label titration period and the blind double-blind treatment period (17-week study in patients with chronic back pain b aja) Period of treatment with double blind (dosage of 12 weeks) Reaction Titration of 1 Tablet of 2 Adverse Placebo Tablets open label VICODIN CR VICODIN CR (N-172) (term (dosage of (N = 170) (N = 169) preferred) up to 3 weeks) all inscribed (N = 770) Constipation 29% 4% 7% 2% Nausea 26% 5% 9% 3% Somnolence 14% 4% 2% 0% Itching 10% 1% 0% < 1% Pain of 9% 5% 4% 6% head Dizziness 8% 1% 2% 1 Vomiting 8% 3% 4% 1% Fatigue 6% 0% 2% < 1% Diarrhea 2% 4% 5% 3% i Table 2. Adverse reactions emerging from treatment reported in > 5% of patients during the period of double-blind treatment (17-week study in patients with osteoarthritis) Period of treatment with double blind (dosage of 17 weeks) Adverse reaction (term 2 Placebo Tablets (N = 443) preferred) VICODIN CR (N = 430) Constipation 44% 14% Nausea 29% 10% Drowsiness 13% 4% Itching 10% 4% Dizziness 10% 3% Vomit 8% < 1% Fatigue 6% 3% Insomnia 6% 3% Arthralgia 5% 4% Diarrhea 5% 4% Limb pain 5% 4% Acute Pain Study In a study of acute pain with double-blind, placebo-controlled surgery of bunionectomy of the first metatarsal, ost-unilateral, patients were randomly chosen to receive 1 tablet of Vicodin CR twice daily, 2 tablets of Vicodin CR twice daily or placebo for 2 days (total of 4 doses). Adverse reactions emerging from treatment reported in > 5% of patients during the study of acute bunionectomy were presented in the Table F 12 Table 3. Adverse reactions emerging from treatment reported in > 5% of patients during the study acute bunionectomy Period of treatment with double blind (2-day dosage) Adverse Reaction 1 Tablet of 2 Placebo Tablets (preferred term) VICODIN CR VICODIN CR (N = 53) (N = 54) (N = 56) Nausea 46% 70% 13% Vomiting 19% 39% 6% Drowsiness 19% 30% 11% Headache 24% 29% 17% Dizziness 26% 23% 0% Itching 11% 16% 0% Anorexia 6% 0% 0% Constipation 9% 9% 4% Diarrhea 21% 5% 0% Generalized itching 0% 5% 0% Rash 0% 5% 2% Open Etigueta Safety Study In an Open Label Safety Study, patients with osteoarthritis or chronic low back pain received 2 tablets of Vicodin CR twice daily for up to 13 months. Adverse events reported in this Open Label Study were similar to those observed in the controlled tests in acute and chronic pain. Adverse events reported in > 5% adverse events reported by (> 1 to < 5%) patients treated with Vicodin CR in the clinical tests organized by the Organ or System Class of edDRA (Medical Dictionary for Normative Activities) not listed above were: Gastrointestinal disorders Abdominal pain, upper abdominal pain, dry mouth, dyspepsia, tooth pain General disorders and administration site conditions Asthenia, peripheral edema, pain, pyrexia Diseases and epidemics . Gastroenteritis, viral gastroenteritis, sinusitis, urinary tract infection] Complications of injury, poisoning and procedural Drop Disorders of skeletal muscle and connective tissue Muscle spasms, muscle pain Nervous system disorders Lethargy, sedation Respiratory, thoracic and mediasti disorders Cough, pharyngo-laryngeal pain Skin and subcutaneous tissue disorders Hyperhidrosis Vascular disorders Redness, embarrassment, hypertension Other less common adverse reactions that were observed in < 1% of the Vicodin CR tests not listed above include the following in alphabetical order (similar terms were combined as appropriate): adjustment disorder, lack of affection, agitation, amnesia, anemia, arthritis, asthma, asthma , atriai fibrillation, bladder disorder, blindness, phosphore, increased blood alkaline rate, abnormal blood / electrolyte, increased blood glucose, decreased blood in the stool, decreased testosterone and estrogen in the blood, bruxism, cardiac arrest, congestive heart failure, stroke, cholecystitis, confusion, deep vein thrombosis, dehydration, depressed consciousness, dermatitis, diverticulitis, drug rash, drug intolerance, drug withdrawal syndrome, dry eye, dysarthria, dysgeusia, dysphagia, dysphonia , dyspnea, increased energy, enuresis, epididymitis, epistaxis, erectile dysfunction, erythema, euphoric mood, sensation anorm to the sensation of drunkenness, sensation of change of body temperature, sensation of relaxation, alteration of walk, gastric ulcer, hemorrhagia, gastritis, gastrointestinal disorder, hematoma, haemoplasia, hemorrhoids, hallucination, hearing impairment, increased heart rate, liver uptake increased, hypo, hypostia, hypoglycemia, hypotension that includes orthostatic hypotension, hypoxia, increased appetite, infection, injury, logorrhea, menstrual disorder, mental deterioration, motor dysfunction, muscle spasms, muscle weakness, myocardial infarction, m ios itis, neoplasm malignant, nephrolithiasis, neuropathy, nightmare, palpitations, pancreatitis, paraesthesia, paranoia, peripheral vascular disorder, photophobia, piloerection, prostatic disorder, pulmonary embolism, rectal fissure, renal insufficiency, respiratory rhythm ratori or diminished, restless legs syndrome, catarrh, seasonal allergy, sexual dysfunction, syndrome of apnea of the year, sleep disorder, substance abuse, suicide attempt, syncope, thrombocytopenia, tinnitus, transient deafness, tremors, urinary retention, abnormal urine analysis, urticaria, blurred vision, weight fluctuation.

Adverse Events with Vicodin of Immediate Release In addition to those mentioned above, the following experiences were reported in patients receiving Vicodi and immediate release but not observed in clinical trials with Vicodin CR.

Blood and lymphatic disorders Agranulocytosis, thrombocytopenia Ear and labyrinth disorders Auditory deterioration or permanent loss, predominantly in patients with chronic overdose.

Ethanol interaction In in vitro studies of ethanol effects in Vicodin CR the release of hydrocodone and acetaminophen was not modified in the presence of ethanol (0% and 40% ethanol) within the first 3 hours but showed slight elevations in amounts released in 5 a 7 hours. No dose discharge of hydrocodone was shown in vitro within the first 2 hours in the dissolution media (0.0 in HCl and simulated gastric fluid) containing 4%, 20%. and 40% ethanol. An in vivo study examined the effect of the co-administration of 240 mL of 40%, 20%, 4% and 0% ethanol on the bioavailability of an individual tablet of Vicodin CR, in healthy subjects, on an empty stomach. No dose discharge was observed for Vicod i n C R when co-administered with ethanol. The average maximum plasma concentration (Cmax) of hydrocodone and acetaminophen aurr is << 25% when Vicodin CR was co-administered with up to 40% ethanol. The area under the concentration curves gave a plasma time (AUC) for hydrocodone and acetaminophen administered with different concentrations of ethanol were equivalent to those of Vicodin CR alone (ie, co-administration with 0% ethanolj. variability in exposures of hydrocodone and acetaminophen (C and AUC) by the co-administration of ethanol, or there was a relationship between the changes in Cmax and the observed clinical changes (pupilometry, Ramsey Sedation).

Liver deterioration The effects of hepatic impairment on the pharmacokinetics of Vicodin CR were studied in 24 subjects: 8 subjects with normal hepatic puncture, 8 subjects with chronic stable mild liver impairment (Child-Pugh Classification A) and 8 subjects with moderate stable chronic liver impairment ( Child-Pugh Classification B). Following the oral administration of an individual Vicodin CR tablet, the average Cmax and A UC hydrocodone values were similar in normal subjects and subjects with immoderate light liver impairment. The mean Cmax and AUC values of acetaminophen were similar in normal subjects and subjects with mild hepatic impairment, and 34 to 42% higher in subjects with hepatic impairment, than in subjects with hepatic impairment.

Gender There were no differences in pharmacokinetics in hydrocodone and acetaminophen, or clinically significant differences in efficacy outcomes or incidence of adverse reactions between men and women in clinical studies with Vicodin CR.

Metabolizers Deficient of Cytochrome P450 2D6 The CYP2D6 polymorphism had no statistically significant impact on the pharmacokinetics of hydrocodone. Seven percent of patients with genotype receiving Vicodin CR in an acute bunionectomy study (6/90) and a chronic osteoarthritis study (21/300) were poor metabolizers. No differences in effectiveness were observed between the deficient and competent metabolizers of cytochrome P450 2D6.

Vicodin CR is an extended-release tablet, orally administered. Each extended-release tablet contains 1 5 mg of hydrocodone bitartrate and 500 mg of acetaminophen. After the release of the nominal drug load, a tablet liner is removed in the stool. Hydrocodone bitartrate hemipentahydrate is an analgesic and anticonvulsant opioid and occurs as fine crystals, white or as a crystalline powder. It is affected by light. The chemical man is: hydrate (2: 5) tartrate (1: 1) of 4,5 a-epoxy-3-methoxy-17-methylmorphinan-6-one. The molecular formula is Ci8H2i N03C4H606- 2½ H20 and the molecular weight is 494.50. The chemical structure of hydrocodone bitartrate is: Acetaminophen, 4'-hydroxyacetanilide, a slightly more bitter, white, odorless, crystalline powder, is a non-opioid analgesic and antipyretic, without salicylate. The molecular formula is C8H9N02 and the molecular weight is 151. 16. The chemical structure of acetaminophen is: NHC0CH 3 In addition, each tablet contains the following active ingredients: stearic acid, croscarmellose sodium, copovicone, poloxamer 188, hydroxyethylcellulose, ferric oxide (red), hydroxypropylcellulose, polyethylene oxide, carnauba wax, acetone, butylated hydroxytoluene (BHT), Opadry ( white), hydroxypropylmethylcellulose 2910, cellulose acetate, polyethylene glycol 3350, povidone, purified water, magnesium stearate, colloidal silicon dioxide, and sodium chloride.

Clinical pharmacology Mechanism of action Hydrocodone is a semisynthetic opioid analgesic and anticonvulsant with multiple actions qualitatively similar to those of other mu opioid receptor agonists. Many of these involve the central nervous system and the soft muscle. The precise mechanism of action of hydrocodone and other opioids is not known, although it is thought to be related to the existence of opioid receptors in the central nervous system. The analgesic action of acetaminophen involves peripheral influences, but the specific mechanism is still indeterminate. The antipyretic activity is mediated through hypothalamic heart regulation centers. Acetaminophen inhibits the synthetase of prostaglandin. The therapeutic dose of acetaminophen has negligible effects on the cardiovascular or respiratory systems; however, the toxic dose can cause circulatory failure and rapid, shallow breathing.

Pharmacodynamics The exposure-response relationship was determined from three acute pain studies chosen at random, with double c ego, controlled by placebo in more than 450 patients receiving 1 tablet of 1 tablet of Vicodin CR, 2 tablets of Vicodi n CR , Immediate Release Tab (10 mg hydrocodone bitartrate / 325 mg acetaminophen) or placebo. A direct relationship was found between the exposure of hydrocodone and combined acetaminophen (plasma concentration) and clinical response (pain intensity on a visual analogue scale) after explaining the time course of the placebo response (Figure 1).

The exposure-response ratio continued between the effective plasma concentration (plasma concentrations of adjusted-strength hydrocodone and combined acetaminophen) and the clinical response indicates a proportional dose-response between one and two tablets of VICODI N CR. The estimated difference in pain intensity on a visual analogue scale, after explaining the time course of the placebo response, is approximately 4 mm and 30 mm for one tablet and two Vicodin tablets | C R, respectively.

Pharmacokinetics Absorption: Following the oral administration of Vicodin CR in healthy subjects, the Cm to x for hydrocodone was achieved between 4 to 7 hours. Average plasma acetaminophen concentrations increase rapidly and peak at approximately 1 hour. Cm to x and AUC for both hydrocodone and acetaminophen were proportional to the dose after individual administration of 1, 2 and 3 tablet doses (Figure 2).

The inactive state for concentrations of hydrocodone and acetaminophen was achieved for 24 hours with minimal accumulation when Vicodin CR was administered every 12 hours. There was less fluctuation between peak and fall plasma concentrations for Vicodin CR than for the immediate release tablet (10 mg bolus or hydrocodone / 325 mg acetaminophen) every four hours (Figure 3).

Food Effect: Vicodin CR can be taken with or without food, since the i Food has no effect on Cm to x or AUC of hydrocodone and acetaminophen.

Distribution: Hydrocodone is structurally similar to other opioid analgesics (hydromorphone and oxycodone). Therefore, it is not anticipated that hydrocodone will bind extensively to plasma proteins.

Following the administration of Vicodin CR, the apparent volume of distribution for hydrocodone ranged from 277 to 714 L in subjects and healthy patients with moderate to severe pain. It was reported that acetaminophen was 15-21% bound to higher drug concentrations were associated with overdose (280 pg / mL). Following the administration of Vicodin CR, the apparent volume of distribution for acetaminophen ranged from 78 to 245 L in healthy subjects with moderate to severe pain.

Metabolism: Hydrocodone exhibits a complex pattern of metabolism that includes N-demethylation (norhydrocodone), OO-ddeemmeettiillLation (hydromorphone) and 6-keto reductions to the corresponding 6- (alpha) and 6- (beta) -hydroxy metabolites. Acetaminophen is metabolized mainly by the liver (conjugation).

CLINICAL STUDIES The efficacy and safety of Vicodin CR tablets in acute and chronic pain were evaluated. A total of 1968 patients received Vicodin CR in studies of chronic low back pain, non-cancer pain, osteoarthritis pain or post-surgical pain (buniohectomy) and a long-term Open Label Safety Study.

Study of seventeen (17) weeks in patients with chronic low back pain Patients with a diagnosis of chronic low back pain (CLBP) (for a duration of at least 6 months) who are suboptimally responsive to their current therapy entered a three-week open-label dose titration period (dose increased to 2 tablets twice a day). Most d; the patients enrolled were Caucasian (86%) and the majority of the patients were female (59%). The average age f L e of 49.2 years, with a variety from 21 to 76 years. Of the patients who completed the open label period, the average mark +/- SD VAS (0-1,00, with 0 mm = no pain and 100 mm = worst pain imaginable) in the monitoring was 77.0 +/- 1 3.9 and in the baseline (starting with the double-blind period) was 25.1 +/- 14.8 2 tablets of Vicodin CR, 24.4 +/- 13.1 1 tablet of Vicodin GR and 24.3 +/- 1 5.2 placebo treatment groups, respectively. Sixty-six percent of enrolled patients were able to be titrated at a tolerable dose and were randomly chosen in a 12-week double-blind maintenance period with 2 tablets of Vicodin CR, 1 tablet or placebo. During the first 7 days of the double-blind maintenance period, patients treated with placebo gradually reduced their dose of Vicodin GR in order to minimize opioid withdrawal symptoms in the placebo subjects. Of the 51 1 randomly chosen, 169 were randomly chosen for 2 Vicodin CR tablets twice daily, 1 70 for 1 Vicodin CR tablet twice daily and 172 for placebo. Seventy-one percent of the subjects treated with Vicodin C R completed the 12-week treatment period compared with cinchor and two percent of the subjects treated with placebo.

The primary efficacy analysis for the double-blind maintenance period was the valuation of the average change in the CLBP intensity assessment by VAS of the subject from the double-blind baseline until the final evaluation. A significantly lower increase in pain marks was observed in the treatment group with 2 tablets of Vicodin CR when compared to the placebo treatment group as shown in Figure 4.

The proportion of patients with various levels of pain reduction from the baseline to the endpoint of the study is shown in Figure 5.

Study of seventeen (17) weeks in patients with osteoarthritis Eight hundred seventy-three patients with hip or knee osteoarthritis (OA) were randomly chosen for 2 tablets of Vicodi i C R twice daily or placebo in a double-blind, placebo-controlled study. The study consisted of a 3-week double-blind titration period, followed by a 12-week maintenance period, a one-week reduction period, and a one-week follow-up period. 440 patients were randomly chosen for Vicodin CR and 433 were randomly chosen for placebo; 489 completed the study (238 patients for Vicodin C R and 251 for placebo). The majority of patients were Caucasian (84%) and the majority of patients were female (64%). The average age was 58.6 years, with a range from 23 to 80 years.

Treatment with 2 Vicodin C R tablets twice a day resulted in an improvement in the valuation of pain intensity scores for arthritis of the average subject from the line you have to the 12th week of maintenance when compared to; placebo (p = 0.055) and significantly increased the proportion of patients with a reduction of at least 50% in pain marking from the baseline (37% of Vicodin CR against 29% of placebo). For various degrees of improvement from the baseline to the end point of the study (maintenance week 12), Figure 5 shows the proportion of patients achieving that degree of improvement. The figure is cumulative, so that patients whose change from the baseline is, for example, 50%, are also included in each level of improvement under 50%. Patients who did not complete the study were assigned with 0% improvement.

Study of acute ionectomy bun In a 2-day randomized, double-blind, placebo-controlled, multi-center study in patients with bunionctomy surgery status of the first metatarsal, posterolateral, unilateral, 163 patients received one or 2 tablets of Vicodi n CR or placebo twice a day. Of the 163 patients enrolled, it was; they chose at random 1 10 for Vicodin CR and 53 chose at random for placebo; 159 patients completed the study (106 patients for Vicodin C R and 53 for placebo). The majority of patients were Caucasian (80%) and the majority of patients were female (89%). The average age was 42.1 years, with a range from 21 to 65 years. For the end point of primary efficacy, there was a statistically significant reduction in pain intensity with 2 Vicodin CR tabs twice daily compared to placebo in the first 12-hour period after the dose (sum of intensity differences of the pain [SPI D]) (see Figure 7). The onset of pain relief occurred within one hour in patients taking 2 tablets of Vicodin CR.

Open label security study In an open-label, multi-center safety study, patients with osteoarthritis or chronic low back pain received 2 tablets of Vicodin CR for up to 13 months. There were 431 patients who were treated in the study; 1 91 (44%) completed one year and 242 (56%) completed 6 months of treatment. There were 246 patients (57%) who discontinued the study prematurely, including 1 12 (26%) of abstinence due to adverse events and 32 (7%) due to lack of efficacy.

As described above, a patient's quality of life is often adversely affected by; the pain. In addition, this quality of life is associated with the loss of labor productivity, which impacts both the patient and his boss adversely. The present invention provides methods to improve quality of life and related conditions through the formulation of hydrocodone / acetaminophen (HC / APAP C R) extended release, twice a day, safe and effective. Such formulations are described in the patent application of E (JA 10/949, 141, (US 20050158382), 1 1 / 625,705 (US 20070190 142), 1 1 / 780,625 (US 20090022798), 1 1 / 737,904 (US). 20080031 901) and 1 1 / 737,914 (US 20070281018), all of which are hereby incorporated by reference in their entirety for all purposes In the most preferred embodiment, the formulation comprises approximately 15 mg of pentahemihydrate bitartratol hydrocodone and approximately 500 mg of acetaminophen.

The following examples are provided to illustrate the preferred embodiments of the inventions, and should not be considered to limit their scope. Thus, even if treatment and quality of life improvements for osteoarthritis and lower back pain are specifically provided, the invention should not be considered to address any of these pain conditions, however, other conditions should be included. Adas with pain known to a person skilled in the art. In addition, these formulations specifically address moderate to severe pain conditions, however, one skilled in the art will appreciate that this formulation may be useful for treating other related conditions.

Example I: Effects of extended-release hydrocodone / acetaminophen for 12 hours on arthritis and quality of life in patients with osteoarthritis: a 12-week, randomized, placebo-controlled study Methods: A placebo controlled study was conducted! double-blind, multiple-center, randomly selected in patients with moderate to severe chronic hip or knee pain (n = 873). Patients received 2 tablets of 15 mg of extended-release hydrocodone / 500 mg of acetaminophen (HC / A PA PCR) or placebo twice a day. The results of primary efficacy showed reductions in pain intensity and are presented separately together with safety analyzes and are not included in this presentation. Secondary efficacy measures included overall assessment of the subject and physician (SGA and PGA) of arthritis sta- tus, the Osteoarthritis Index of the University of Western Ontario and Mc Asters (WOMAC ™), and the quality of Life ( SF-36v2 ™). These endpoints were reported here.

Results: In week 12, statistically significant improvements were observed in the brand, total WOMAC ™ (p = 0.001) and the 3 subscales [pain, stiffness, physical function (p = 0.001 in all measurements)] with HC / A PA PCR treatment. Similarly, in the final evaluation, the physical component summary and the body pain sub-domain of SF 36v2 ™ showed statistically significant improvements from baseline (p = 0.044 and 0.004, respectively) with HC / APAP CR compared with placebo. In addition, statistically significantly greater benefits with HC / APAP CR were also observed in SGA and | PGA of arthritis status at week 12 (p <0.001).

Conclusions: Treatment of HC / APA P CR was associated with statistically significant improvements in the WOMAC ™ instrument and the SF-36v2 ™ universal measurement. These results suggest that HC / APAP CR can not only provide effective analgesia, but also improvements in quality of life in patients with moderate-severe OA pain.

Example II A double-blind, multi-center, placebo-controlled trial that compares the analgesic efficacy of hydrocodone / acetaminophen tablets with extended release and plasma in patients with osteoarthritis Methods: A randomized, double-blind, placebo-controlled, placebo-controlled study was conducted in 873 patients with moderate to severe chronic hip or knee OA pain. The study was divided into 4 periods: monitoring / washing for up to 4 weeks, titration for 3 weeks, maintenance for 12 weeks, and study drug reduction for 1 week. 430 patients received 1 5 mg of HC 13/500 mg of extended release APAP twice daily and 443 patients received placebo twice daily. The primary efficacy variable was the percentage change from the baseline (just before the start of the 3-week titration) | to week 12 of maintenance (final planned assessment in the maintenance period) in the assessment of arthritis pain intensity (A PI) of patients using a visual analogue scale of 100 mm. The following methods were used to attribute the missing objects: observed baseline transported forward (BOCF), and a mixed imputation method using BOC F tap and the last observation carried forward (LOCF). We also compared safety measures, including adverse events between the treatment groups.

Results: Compared with placebo, HC / APAP CR demonstrated the numerical improvement (p = 0.055). in API mark that BOCF uses for imputation of missing data. However, a mixed imputation of the primary endpoint (using BOCF for subjects who were prematurely discontinued due to AE or who did not have any post-baseline assessment, and LOCF for patients who discontinued prematurely for any other reason), demonstrated that HC / APAP CR significantly improved statistically API compared to placebo (p = 0.008). Adverse events that occurred in > 5% of patients in the HC / APAP GR group and that occurred with a significantly higher incidence when compared to placebo were: constipation, nausea, vomiting, dizziness, drowsiness, insomnia and pruritus.

Conclusions: The HC / APAP CR formulation of extended release twice a day was an effective treatment that was well tolerated in patients with moderate to severe chronic OA pain.

Example III Long-term impact of labor productivity related to value among patients with low back pain who take 12-hour extended release hydrocodone / acetaminophen tablets Methods: As part of a more arga clinical trial reported elsewhere, the Workplace Productivity and Activity Disability (WPAI) instrument was administered in the baseline and weeks 24 and 56 to measure reduced productivity and disability. General work due to health. The economic impact of improved labor productivity and overall work disability due to health after treatment of HC / APAP CR was calculated as the difference in cost (when using the 2007 US average of weekly salary of $ 885) from the baseline until weeks 24 and 56. Analyzes were also conducted by gender and pain intensity (numerical rating scale 0-10, NRS).

RESULTS: In patients with LBP, the impairment worsen working due to health decreased from the baseline by 22% in week 24 and 18% in week 56. This translates to estimated average cost savings per employee of $ 4738 in the week 24, and $ 8864 in week 56. Similarly, general work disability due to health decreased from baseline by 24% at week 24 and 17% at week 56. This translates into savings average potentials for the heads of $ 4,992 and $ 8233 for weeks 24 and 56. When the study population was stratified by gender, the cost savings of work incapacity generated is the heads were estimated at $ 4438 in week 24 and $ 8478 week 56 for female employees and $ 2959 and $ 7137 for male employees. When classified by severity of pain, the productivity of patients with moderate (N RS 4-6) and severe pain (NRS 7-10) improved with cost savings of $ 1671 (moderate) and $ 4226 (severe) in week 24 In week 56, productivity benefits continued with cost savings of $ 5370 (moderate pain) and $ 8529 (severe pain).

Conclusions: As assessed by the WPA I instrument, this cost analysis demonstrated the improved work productivity of extended release HC / APAP CR after 24 and 56 weeks of treatment in patients with LBP. This analysis can provide useful information for bosses and their workers who suffer from | LBP moderate-severe.

Example IV Impact of productivity while at work (with presence) among patients with osteoarthritis taking 12-hour extended-release hydrocodone / acetaminophen tablets at 56 weeks Methods: As part of a clinical trial plus the rga carried elsewhere, the instrument was administered labor productivity and inability of activity (WPAI) in the baseline and weeks 24 and 56 to measure productivity and general work disability due to health in patients with chronic moderate-severe pain. The economic impact of improved labor productivity and total work disability due to health after HC / APAP CR treatment was calculated as the difference in cost (when using the average weekly US salary of Lo07 of $ 885) from baseline to week 24 and week 56 Analyzes by gender and intensity of pain (scale of numerical classification 0-10, NRS) were also conducted.

Results: Among OA patients, the disability while working due to health decreased from baseline by 12% in week 24 and 15% in week 56. This translates to an average estimated cost per employee of $ 2,549 in week 24, and $ 7434 in week 56. Total disability due to health decreased from baseline by 11% in week 24 and 15% in week 56. This translates into average potential savings to the heads of $ 2332 in week 24 and $ 7254 in week 56. When the study population was stratified by gender, the total labor cost savings were higher in women than in men by $ 1524 in week 24 and by $ 1340 in week 56 Classified by baseline pain severity severity, severe pain patients (NRS 7-10) had cost savings in excess of $ 2555 and $ 3159 in weeks 24 and | 56, respectively, compared to patients with moderate linear base pain (NRS 4-6).

Conclusions: This cost analysis, as assessed by the WPAI instrument, demonstrated improved productivity of H C / A PA P C R 12-hour extended release while in a job after 24 and 56 weeks of treatment in patients with | OA. This analysis can provide valuable information for jetes and their workers who suffer from moderate to severe chronic pain Example V: Assessment of disability level and sleep interference in patients with moderate to severe chronic low back pain treated with hydrocodone / acetaminophen 12-hour extended-release tablets: a phase 3 abstinence test Published studies report that the prevalence of chronic low back pain (CLBP) in E. U.A. it is between 4-14%. Beyond pain control, the CLBP treatment goal also improves the level of disability and quality of sleep.

Methods: A phase 3 abstinence study evaluating the treatment of hydrocodone / acetaminophen (HC / A PA PCR) 12-hour extended release in subjects with CLBP, consisted of the following phases: washing / monitoring, open label of active drug of 3 weeks (OL), with a double blind of 12 weeks (DB) where subjects were randomly chosen for placebo, 1 or 2 tablets of HC / APAP CR twice a day, and reduction / follow-up Primary endpoint designs and study design were reported elsewhere. Additionally, the level of disability and sleep interference related to pain were assessed and reported here.

To assess the levels of disability, the subjects were given the Roland-Morri disability questionnaire. i (R MDQ), a self-administered questionnaire of 24 points, in the OL and DB baselines and the final visit. Sleep interference was examined at these time points, with additional assessments at weeks 2, 6, and 12.

RESULTS: During the OL period, improvements were demonstrated in the incapacity of the subjects chosen at random by reductions in RMDQ marks (average percentage change: -52%) from the OL base line to the DB baseline. Additionally, the average reduction in the assessment of the subject of pain interference mark related to pain from the baseline OL to the fineil of the OL period was 4.0 for all the subjects chosen at random in the DB period.

During the DB period, both groups of HC / APA P CR demonstrated a statistically significantly lower average percentage change change in R M DQ scores than the placebo group, from the DB baseline to the final visit. More specifically, the average percentage increase for RMDQ marks in the HC / APAP CR tablet group was 12% compared to 244% in the placebo group (p <0.001). Simi- larly, a significant average increase was observed with a double-blind baseline until the final evaluation of the subject's CLBP intensity assessment (VAS). The safety was evaluated by adverse event assessment (AE). All reported results are from the double blind period.

RESULTS: 51 1 subjects were randomly chosen (51 3 randomly selected, 51 1 received> 1 dose); the data was evaluated for 507 for efficacy. The majority of the subjects were women (58%) and whites (58%); the average age of 48 years. The baseline variables were similar among the 3 groups. The average change from baseline CLBP intensity was statistically significantly lower in subjects in each group of HC / APAP CR than in the placebo group (8.6 ± 2.07, 2 tablets, 1 3.3 ± 2.07, 1 tablet vs. 22.2 ± 2.04 , placebo; p <0.05). No statistically significant difference was observed between the HC / APA P C R groups. For most secondary end points, the treatment of 2 tablets of HC / APAP CR demonstrated numerical advantage against the treatment of one tablet, with statistical superiority for few analyzes. 89/169 (53%) subjects in 2 tablets of HC / APAP CR, 75/1 70 (44%) in one tablet, and 79/172 (46%) in the group of plé babo reported = 1 AE. AE in > 5% of subjects in any treatment group had nausea, constipation, diarrhea, headache. 9 subjects reported serious AE (2 in each group of HC / A PA P CR; 5 in the placebo group); 28 discontinued due to AE (3% in the placebo group, 6% in the one-tablet group, 7% in the 2-tablet group).

Conclusions: Both doses of HC / APAP CR resulted in significantly lower intensities of CLBP versus placebo. The HC / APAP CR safety profile was consistent with the known profile of a product containing mu opioid receptor agonist.

Example VII Effects of extended release hydrocodone / acetaminophen. 12 hours in work productivity related to pain; a sub-analysis from an open label study of 56 weeks Conditions of chronic pain, such as osteoarthritis (OA) and chronic mechanical low back pain (CLBP), among active workers, cost the heads ~ $ 61.2 billion / year in lost productive time, which includes both reduced performance while Are work and work days lost (absenteeism). A study of productivity time lost from an open-label study of 56 weeks was conducted to calculate the: potential economic effects of HC / APAP CR treatment for managers.

More specifically, an estimated 50 million Americans suffer from chronic pain, and 41% of patients reported that their pain is not adequately controlled. Nicholson B, Ross E, Weil A, Sasaki J, Sacks G. Treatment of moderate to severe chronic non-malignant pain with morphine sulfate capsules coated with extended release polymer. Curr Med Res Opin. Mar 2006; 22 (3): 539-550. Chronic pain is the most common cause of long-term disability and is associated with reduced physical, psychological, and social well-being. Reid MC, Engles-Horton LL, Weber MB, Kerns RD, Rogers EL, O'Connor PG. The use of opioid medications for chronic non-cancer pain syndromes is in primary care. J Gen Intern Med. Mar 2002; 1 7 (3): 173-179; Longo LP, Parran T, Jr., Johnson B, Kinsey W. Custody: part II. Identification and management of the patient seeking drugs. Am Fam Physician. Apr 1 5 2000; 61 (8): 2401 -2408. Conditions of chronic pain, such as osteoarthritis (OA) and chronic mechanical low back pain (CLBP), among active workers costs the heads ~ $ 61.2 billion / year in lost productive time, which is mainly caused by performance reduced while at work as opposed to lost work days (absenteeism). Stewart WF, Ricci JA, Chee E, and others. Lost productive time and cost due to common pain conditions in the E. U.A workforce. JAMA 2003; 290: 2443-2454. OA is the most common type of arthritis (also known as degenerative joint disease), which affects 12% of adults in the U.A.A with age of 25 to 74 years. Barnes EV, Edwards N L. Treatment of osteoarthritis. South Med J. Feb 2005; 98 (2): 205-209; Lawrénce 'RC, Felson, DT, Helmick CG, and others. Estimates of the prevalence of arthritis and other romantic conditions in the United States: part I I. Arthritis Rheum. 2007 Dec 28; 58 (l): 26-35 [Epu b before printing]. poster 143. The results reported here are from a secondary endpoint selected from this study that used the instrument of labor productivity and inability of activity (WPAI) to calculate the potential economic effects of treatment with HC / APAP CR in a population of patients with moderate to severe pain.

Methods: As part of a more clinical trial reported elsewhere, the productivity and inability to activity (WPAI) instrument was administered at the baseline and weeks 24 and 56 to measure reduced productivity and I n general labor capacity due to health. The results were reported as a percentage of lost productivity time and estimated economic impact to the bosses. When using the average weekly salary of E. U.A. of $ 861 in 2006, the average costs of reduced productivity and general work disability due to health were calculated. The economic impact of improved labor productivity and general work disability due to; The salt after treatment with HC / APAP CR was calculated as the difference in cost from baseline to week 24 and week 56.

Specifically, this open-label, multi-center study was designed to assess the safety and tolerability of HC / APAP CR tablets of 15 mg / 500 mg for 12 hours administered twice daily in patients with moderate chronic non-malignant pain. Severe exemplified by OA pain of the hip or rod il la, or C LBP. Here we report the results of a sub-analysis of selected secondary end points of work productivity related to pain.

The study was conducted from July 2005 to December 2006. 431 patients enrolled in 74 study sites. Patients who did not meet the selection criteria did not participate in the washout period, and the analgesic use was discontinued for 5 half-lives or 2 days, whichever was longer. Patients returned to the study site and enrolled in the 7-day titration period if they met the eligibility criteria, including a mark of 4 on the subject's pain intensity scale. During the titration period, patients take a HC / APAP CR tablet once a day for 3 days, followed by a HC / APAP CR tablet twice a day for 4 days.

Following the titration period, the patients returned to the study site and entered the maintenance period, during which they took 2 tablets of HC / APAP CR twice a day for 56 weeks.

After the maintenance period, patients entered the 1-week study drug reduction period, during which patients received a tablet of HC / APAP CR twice a day for 4 days, followed by a tablet once a day for an additional 3 days, after which HC / APAP CR was discontinued (Figure 8). A visit was conducted follow-up 1 week after discontinuation of study drug.

Main inclusion criteria Patients eligible for participation in the study were between 21 and 75 years of age. Patients satisfied the ACR classification criteria for OA of the hip or knee and experienced mechanical lower back pain, under the twelfth thoracic vertebra greater than 3 months.

Intensity of subject pain scale by a Likert scale of 11 points (0 = no pain, 10 = worst pain imaginable) was = 4 in the baseline visit.

Statistical methods All costs were represented in dollars of ELU.A I. of the 2006 and were calculated using statistical software SAS v9.1 or v8.2.

Efficacy analyzes were conducted including all the data as observed. That is, no imputation was made for the data that was missing for a scheduled visit.

An evaluable data set of efficacy excluded all 16 patients from an individual study center because some of the patients were verbally aided by study center staff in translating some portions of the efficacy assessment questionnaires. This population is considered the primary population to report summary statistics.

Efficacy reviews The WPAI instrument is a questionnaire used to measure reduced productivity and general work disability due to health, and was administered in the baseline and in weeks 24 and 56 Patients were asked to assess how their health problems impacted productivity while working and how their health affected their ability to do regular daily activities on a scale of 0-10 (0 = no effect, 1 0 = total work / activity prevented) ) The results were reported as a percentage of lost productivity time and the estimated economic impact to the bosses.

When using the average weekly wage of E. U.A. of 2006 of $ 861 (reported by the Bureau of Labor Statistics), the average costs of reduced productivity and general work disability due to health were calculated.

The economic impact of improved labor productivity and overall work disability due to health after treatment with HC / APAP CR was calculated as the differential in cost from baseline to week 24 and week 56.

Patient's disposition A total of 431 patients received at least one dose of study drug and were included in the treatment to treat (ITT) data set. The majority of ITT patients in the study were women (60%) and whites (91%). The average age was 54 years and the age ranged from 21 to 76 years. The summary of baseline characteristics (ITT data set) and demographics of all patients is presented in Table 5.

Table 5 Demographic characteristic HC / APAP CR N = 431 Sex [n ()] Female 259 (60) Male 172 (40) Race [n (%)] White 391 (91) Black 29 (7) Asian 1 (< 1) Another 10 (2) Age (years) N 431 Average ± SD 54.0 ± 11.19 Minimum-maximum 21.0-76.0 Height * (cm) N 429 Average ± SD 169.2 ± 10.16 Minimum-maximum 135.0-198.0 Weight * (kg) N 431 Average ± SD 91 4 ± 25.20 Minimum-maximum 41.0-225.0 * Online baseline Results: Work-related disability decreased from baseline by 17.4% in week 24 and 16.6% in week 56. This translates into estimated cost savings (per employee) to heads of $ 3527 in week 24, and $ 8019 week 56. Simi- larly, the general work disability due to the salt decreased from the baseline by 17.5% in week 24 and 1 5.8% in week 56. This translates into average potential savings to the heads of $ 3614 in week 24 and $ 7596 in week 56. Absenteeism decreased by 1. 1% in week 24 and by 0.04% in week 56.

Specifically, the results of WPAI are as follows: Disability while working due to health decreased from the baseline by 1 7.4% in week 24 and 16.6% in week 56. This translates into estimated cost savings (per employee) to heads of $ 3527 in the week 24 and $ 801 9 in week 56. Similarly, the general work disability due to health decreased from the baseline by 17.5% in week 24 and 1 5.8% in week 56. This translates into average potential savings to the heads of $ 3614 in week 24 and $ 7596 in week 56. Work time lost due to health decreased by 1. 1% in week 24 and by 0% in week 56. The results are summarized in Figure 6 and Table 6.

Table 6 illustrates the baseline values and the average change from the baseline to the 24th and 56th weeks in labor productivity and the activity disability questionnaire (set of efficacy data).

Table 6 We are going to help you to pray CR of extended release for 12 hours after 24 and 56 weeks of treatment in patients with OA and CLBP. 12-hour extended release hydrocodone / acetaminophen effects on pain-related physical function, work productivity, and sleep quality: an open label study of 56 weeks Osteoarthritis and chronic low back pain (CLBP) | they are common pain conditions that can have a significant negative impact on physical function, work productivity, and quality of sleep. Pain reduction is a primary treatment, however, improvements in sleep, productivity, and / or maintenance of physical functioning are also important. The primary objective was to assess the long-term safety and efficacy of extended-release hydrocodone / acetaminophen (HC / APAP CR). Here, we report the results of the secondary objectives: sleep, function / physical role, and productivity.

Specifically, osteoarthritis (OA) is the most common type of arthritis (also known as degenerative joint disease), affecting 12% of adults in the U.S.A. with ages from 25 to 74 years old. CLBP is low back pain that has persisted for more than 3 months and affects approximately 19% of working adults in the US. The reduction of chronic pain was mited by primary treatment in this study. Secondary objectives included sleep, productivity, and / or performance or physical functioning. The first-line pharmacological treatment for patients with OA or CLBP is typically acetaminophen (A¡PAP) and / or nonsteroidal anti-inflammatory drugs (NSAIDs). [For patients with OA and CLBP whose pain is not effectively managed by APAP or NSAID, combination opioids (containing codeine, hydrocodone (HC), or oxycodone) may be important treatment alternatives. Opioids are an important treatment option for moderate to severe chronic pain. Combination opioids, including HC / APAP, proved to be effective in the treatment of moderate to severe pain syndromes, such as OA and CLBP, but are currently available only in short-acting formulations.

Methods: Detailed information was reported on the primary endpoint and the study design. Secondary end points were assessed using the short pain inventory (BPI), labor productivity and inability to activity (WPAI), and the SF-36 questionnaires that occurred at baseline, weeks 24 and 56. BPI was also administered in weeks 4, 12, and 40.

Specifically, this open-label multiple-center study was designed to assess the safety and tolerability of HC / APAP CR tablets of 12 mg / 500 mg for 12 hours administered twice daily in patients with moderate to severe chronic non-malignant pain. exemplified by OA pain of the hip or knee, or CLBP.

The study was conducted from July 2005 to December of the 2006. 431 patients were enrolled in 74 study sites! Patients who did not meet the selection criteria entered the washout period, and the previous analgesic use was discontinued for 5 half-lives or 2 days, whichever was longer.

Patients returned to the study site and enrolled in a 7-day titration period if they met the eligibility criteria, including a brand of > 4 on the subject's pain intensity scale. During the titration period, patients take a HC / APAP CR tablet once a day for 3 days, followed by a HC / APAP CR tablet twice a day for 4 days.

Following the titration period, patients registered at the study site and entered the maintenance period, during which time they take 2 tablets of HC / APAP CR twice a day for 56 weeks.

After the maintenance period, patients entered the 1-week study drug reduction period, during which patients received a HC / APAP CR tablet twice daily for 4 days, followed by a tablet once a day. day for 3 additional days, after which HC / APAP CR is discontinued (Figure 10). A 1-week follow-up visit was conducted after the discontinuation of the study drug.

Main inclusion criteria Patients eligible for participation in the study They were between 21 and 75 years old.

Patients who met the ACR classification criteria for OA of the hip or knee experienced mechanical low back pain, under the twelfth thoracic vertebra for more than 3 months.

Intensity pain scale of the subject on a Likert scale of 1 1 points (0 = no pain, 10 = worse unimaginable pain) was = 4 at the baseline visit.

Statistical methods Secondary endpoints were assessed using the brief pain (BPI), labor productivity and activity disability (WPAI) inventories, and SF-36 questionnaires that were administered at the baseline, weeks 24 and 56. B was also administered. PI in weeks 4, 12, and 40.

BPI is a validated self-administered 2-page questionnaire used to assess the severity and impact of pain in daily functions. In addition, patients qualify as pain interfered with activity, mood, general walking ability, normal work, relationships with others, sleep, and enjoyment of life during the previous 24 hours. The WPAI instrument is a questionnaire used to measure reduced productivity and general work disability due to health. Patients were asked to assess how much their health problems affected productivity while they worked and how their health affected their ability to do regular daily activities.

SF-36 is a questionnaire used to assess the patient's own health status at the current time as well as in a previous year.

RESULTS: Patients showed improvement in all BPI pain assessments from the baseline to each of the evaluation periods. In particular, patients had less sleep interference (decreased ~ 40-50%) and less interference in the ability to walk due to pain (decreased r30-40%) from baseline to weeks 4, 12, 24, 40 and 56.

In week 24, the disability while working due to health decreased from the baseline by 1 7.4%, and the disability from regular daily activities decreased by 24.7%. In week 56, the disability while working due to health decreased from the baseline by 16.6%, and the inability of dijarias activities decreased 22.3%. General disability due to health decreased by 17.5% in week 24 and 15.8% in week 56 Improvements were observed in the 8 SF-36 domains from the baseline to the study endpoints. Body pain, physical role, and physical functioning domains showed the greatest improvements (average change: 1 8. 13, 17.46, 14.40, respectively) among the 8 domains in week 24. In the final visit, these domains continued to show greater improvements.

Specifically, a total of 431 patients received at least a dose of HC / APAP CR and were included in the set of; Try to try data (ITT).

The majority of patients (ITT) in the study were (60%) and whites (91%). The average age was 54 years and the age ranged from 21 to 76 years. Patient demographics and baseline characteristics were summarized in Table 7.

Table 7 Demographic characteristic HC / APAP CR N = 431¡ Sex [n (%)] Female 259 (60) Male 172 (40) Race [n (%)] White 391 (91) Black 29 (7) Asian 1 (< 1) Another 10 (2) Age (years) N 431 Average ± SD 54.0 ± 11.19 Minimum-maximum 21.0-76.0 Height * (cm) N 429 Average ± SD 169.2 ± 10.16 Minimum-maximum 135.0-198.0 Weight * (kg) N 431 Average ± SD 91.4 ± 25.20 Minimum-maximum 41.0-225.0 * Online baseline Short pain inventory Patients showed improvement in all BPI pain assessments from baseline to each scheduled assessment (Figure 11).

Particularly for the interference group related to pain, patients had less sleep interference (decreased ~ 40-50%) and less interference in the ability to walk due to pain (decreased -30-40%) from the baseline until weeks 4, 12, 24, 40 and 56.

Questionnaire on labor productivity and inability of activity (WPAI) In week 24, disability while working due to health decreased from baseline 17.4%, and the inability to regular daily activities decreased 24.7%.

In week 56, disability while working due to health decreased from baseline 16.6%, and the inability to regular daily activities decreased 22.3%.

The general disability due to health decreased 17.5. { % in week 24 and 15.8% in week 56.

Survey of health status SF-36 The improvements in the 8 sub-domains, and in the physical component summary (PCS) and the mental component summary (MCS) of the SF-36 were observed from the baseline to the study endpoints (Figure 12).

Body pain, physical role, and physical functioning domains showed the greatest improvements (average change: 1 8. 1 3, 1 7.46, 14.40, respectively) among the 8 sub-domains in week 24.

In the final visit, these domains continued to show the greatest improvement.

Conclusion: In this study, patients with OA and CLBP who took HC / APA P CR demonstrated improvement in physical function / role1 and less inability to productivity and pain interference related to pain.

Example IX Efficacy and long-term tolerability of 12-hour extended-release hydrocodone / acetaminophen: a 56-week open-label study Osteoarthritis (OA) and chronic low back pain (CLBP) are the two most prevalent types of chronic non-cancer pain syndromes in E. U.A. Bigos S, Bowyer O, G B. Acute low back problems in adults. Rockville: Agency for Health Care Policy and Research. 1994; Loeser Je. Bonica's Management of Pain. 3rd ed. Lippin Williams & Wilkins; 2001 OA is the most common type of arthritis (also known as degenerative joint disease) that affects 12% of adults in the US. With ages of 25-74 years. Barnes EV, Edwards NL. Treatment of osteoarthritis. South Med J. Feb 2005; 98 (2): 205-209; Lawrence | RC, Felson, DT, Helmick CG, and others. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: part I Arthritis Rheum. 2007 Dec 28; 58 (l): 26-35 [Epub before the printing]. CLBP is low back pain that has persisted for more than 3 months, and affects approximately 19% of workers in the U.A. Martell BA, O'Connor PG, Kerns RD, and others. Systematic review: opioid treatment for chronic back pain: prevalenciá, efficacy, and association with ad icción January 16 2007; 146 (2): l 16-127.

Historically, acetaminophen (APAP) and lanti-inflammatory drugs without spheroids (NSAI D) have been the first-line pharmacological therapy used to treat non-cancer pain syndromes, such as OA and CLBP.

For patients with OA and CLBP whose pain is not | is effectively managed by APAP or NSA | D, combination opioids (containing codeine, hydrocodone (HC), or oxicolone) may be important treatment alternatives.

Opioids are an important treatment option for moderate to severe chronic pain. O S the 3-step analgesic ladder of the World Health Organization. Relief of cancer pain. 1986 Combination opioids, including HC / APAP, have been shown to be effective in the treatment of moderate to severe pain syndromes, such as OA and CLBP, but are currently only available in short-acting formulations An extended-release formulation will potentially increase patient compliance, redthe occurrence of end-of-dose pain, and improve the overall quality of life of individuals with pain syndromes, not of moderate to severe chronic cancer.

The objective of this study was to evaluate the long-term tolerability and safety of 2 tablets of 15 mg hydrocodone / 500 mg acetaminophen (HC / APAP CR) extended-release administered twice daily in osteoarthritis or patients with back pain Chronic mechanical low Methods: Patients were recruited from 74 sites in the E. U .A. 431 patients were enrolled in the titration period and took one HC / APAP CR tablet once a day for 3 weeks followed by a tablet twice a day for 4 days. During maintenance, patients take 2 HC / APAP CR tablets twice a day for 56 weeks. Following the maintenance of 56 weeks, patients had their medication red by 1 week. The patients received rescue medication (acetaminophen) up to 3 times a week. Efficacy was evaluated by a Likert scale of pain intensity, and safety was assessed for the adverse event (AE), vital sign and laboratory assessment.

More specifically, this open-label multiple-center study was designed to assess the safety and tolerability of HC / APAP CR tablets of 15 mg / 500 mg for 12 hours administered twice daily in patients with moderate chronic non-malignant pain. to severe exemplified by OA pain of the hip or knee, or CLBP.

This study was conducted from July 2005 to December 2006, enrolling 431 patients in 74 study sites. Patients who met the selection criteria entered the washout period, and previous analgesic use was discontinued for 5 half-lives or 2 days, whichever is longer.

Patients returned to the study site and were enrolled in a 7-day titration period if they met the eligibility criteria, including a brand of > 4 (out of 10) in the pain intensity scale of the subject. During the titration period, patients take a HC / APAP CR tablet once a day for 3 days, followed by a HC / APAP CR tablet twice a day for 4 days.

Following the titration period, patients returned to the study site and entered the maintenance period, during which they took 2 tablets of HC / APAP CR twice a day for 56 weeks.

After the maintenance period, patients entered the study drug reduction period of one week, during which the patients received a HC / APAP CR table twice a day for 4 days, followed; One tablet was taken once a day for an additional 3 days, after which HC / APAP CR was discontinued (Figure 13). A week's visit was conducted after drug discontinuation Main inclusion criteria Patients eligible for participation in the study were between 21 and 75 years of age.

The patients met the AC R classification criteria for OA of the hip or knee or experienced mechanical lower back pain under the twelfth thoracic vertebra for more than 3 months.

The intensity of pain scale of the subject by a Likert of 1 1 points (0 = no pain, 10 = worst pain imaginable) was > 4 in the baseline visit.

Statistical methods As the objective of this study was to evaluate the safety and i Long-term tolerability of HC / APAP CR, no statistical data were made in this open label single-arm study.

All analyzes of demography, safety, and efficacy were performed using an attempt to treat data set (ITT). All enrolled patients who received a dose of study drug were included in the ITT analyzes.

An evaluable data set of efficacy excluded the 16 patients from an individual study center because some patients were verbally aided by study center personnel in the translation of some portions of the efficacy assessment questionnaires. This population is considered the primary population to report summary statistics.

Rescue Med icamento Rescue medication was not allowed 24 hours before the baseline visit or scheduled study visits; however, patients were allowed to take APAP as a rescue medication (not to exceed 2000 mg / day) during the wash, titration, maintenance, and study reduction periods. All use of A PA P was recorded in the patient's diary. During the titling and maintenance, the rescue was limited to 3 days per week.

Efficacy and safety reviews The intensity of pain was assessed by a Likert scale of 1 1 points (0 = no pain, 10 = worst pain imaginable).

Safety was verified through the study based on assessments of adverse events (AE), physical exams, vital signs, and laboratory tests.

AE was coded using Medical Dictionary I for normative activities (MedDRA) and treatment emergent AEs were tabulated by system organ class (SOC) and MedDRA preferred term.

For laboratory data, average changes were summarized from the baseline for each laboratory variable.

Results: 415/431 patients comprised the conjunct † of evaluable efficacy data reported in the primary analysis population. The intensity of pain decreased from the baseline in all subsequent evaluations (Table 8A).

Table 8A. Average change from the baseline to each visit Pain intensity assessment HC / APAP CR (n = 41 5) pro [med io (Likert scale of 1 1 points) (SD) Baseline 7.7 (1 .39) Ca m bio The most commonly reported treatment AEs (> 10% of patients) were constipation, nausea, headache, and drowsiness (consistent with prior HC / APAP CR tests). 124 (29%) patients discontinued due to AE (s). The most common AEs (> 2% of subjects) that led to discontinuation were nausea, drowsiness, constipation, dizziness, vomiting, headache and fatigue. 25 (6%) patients experienced SAjE (s) OA (4/431; 1%) was the most reported common SAE. The prevalence of use of AE and APAP decreased after the first 30 days of treatment and remained low with time. There were no reports of hepatotoxicity.

More specifically, the results will be described below: Patient's disposition A total of 431 patients received at least one dosage: of study drug and were included in the intention-to-treat (ITT) data set.

The majority of ITT patients in the study were women (60%) and whites (91%). The average age was 54 years and ranged from 21 to 76 years. The demographic summary of all patients is presented in Table 8.

Table 8 Demographic characteristic HC / APAP CR N = 431 Sex [n (%)] Female 259 (60) Male 172 (40) Race [n (%) 1 White 391 (91) Black 29 (7) Asian 1 (< 1) Another 10 (2) Age (years) N 431 Average ± SD 54.0 ± 1 1 .1 9 Min MAX Height * (cm) N 429 Average ± SD 169.2 ± 10.16 Minimum-maximum 135.0-198.0 Weight * (kg) N 431 Average ± SD 91.4 ± 25.20 Minimum-maximum 41.0-225.0 * Online baseline Discontinuation time 57% of the enrolled patients discontinued the study prematurely.

The primary reason most frequently reported for premature discontinuation of the study was an AE (26%; 112/431). 12 additional patients discontinued the study drug prematurely with a secondary reason for emergent AE treatment. 124 (29%) total patients discontinued due to AE; The most common AEs (> 2% of patients) that led to discontinuation were nausea, drowsiness, constipation, dizziness, vomiting; headache, and fatigue. The summary of patient disposition information is presented in Table 9. and drowsiness.

The incidence and prevalence of these common AEs generally decreased over time. The information summary of A E is presented in Table 10.

Table 10 illustrates the summary of treatment emergent adverse events that occur in = 5% of patients in any treatment (ITT data set).

Table 10 61% of patients reported at least one AE related possibly or probably with the treatment. The most common was constipation, nausea, drowsiness, headache, pruritus, dizziness, fatigue, insomnia, vomiting, diarrhea, dry mouth, anxiety, dyspepsia, and sedation. 16% of the AEs were considered severe. Of the severe AEs, nausea was reported most frequently. Other severe AEs included constipation, headache, migraine, influenza, depression, vomiting, and OA, but each was reported in = 2% of patients.

A total of 124 patients (124/431, 29%) reported AE emerging from treatment that at least in part led to premature discontinuation of the study. The most common AE emergent treatment (> 2% of patients) that at least in jacks led to the premature discontinuation of the study were nausea, drowsiness, constipation, dizziness, vomiting, headache and fatigue. Other emergent treatment AEs that led to premature discontinuation were reported by < 2% of patients. 25 (6%) of the patients reported an AE or more serious (SAE), none of which is considered by the researcher to be possible or probably related to the study drug No clinically significant changes were observed from the baseline for any laboratory parameter.

They did not see reports of hepatotoxicity.

The use of APAP rescue medication was greater during the first 30 days and then decreased or remained stable for the duration of the study, suggesting that no tolerance was associated with the use of HC / APAP CR.

Conclusion: HC / APAP CR was effective in the management of chronic non-malignant pain over a period of 56 weeks. The safety profile of Vicodin CR in this study was consistent with that of an agent containing mu opioid receptor agonist. The safety profile of HC / APAP CR was consistent with that of an agent: containing mu opioid receptor agonist.

Example X Safety and efficacy of 12-hour extended release hydrocodone / acetaminophen for acute pain following bunionectomy: a randomized, multi-center, double-blind study The safety and efficacy of 1 or 2 tablets of 15 mg hydrocodone / 500 mg of acetaminophen (HC / APAP CR extended release was evaluated following bunionectomy.) Specifically, the primary objective of this study was to compare the analgesic efficacy j and the safety of HC / APAP CR with placebo in the treatment of moderate to severe pain on the day after primary unilateral, first metatarsal bunionectomy surgery. The secondary objective was to compare the analgesic efficacy and safety of 1 HC / APAP CR tablet twice daily with placebo in the treatment of moderate to severe pain on the day after primary unilateral bunionectomy surgery of the first metatarsal .

Approximately 25 million people suffer from pain that results from an injury or surgery. Deyo RA, Cherkin D, Conrad D, Voin E. Cost, controversy, crisis: low back pain and the health of the public. Annu Rev Public Health. 1 991; 1 2: 141 - 1 56. Due to advances in technology, the most surgical procedures are performed in the outpatient setting. Ambulatory orthopedic procedures require control; Post-operative pain cash. To avoid delayed hospital discharge, reduced recovery post-surgery, and improved patient satisfaction in the outpatient setting, rapid and effective analgesia is crucial for patients with acute postoperative pain. Diaz G, Flood P. Strategies for effective postoperative pain management. Minerva Anesthesiol. 2006; 72: 145-150; Reuben SS, Connelly N R, aciolek H. Post-operative analgesia with controlled-release oxytodon for ambulatory anterior cruciate ligament surgery. Anesth Analg. l999; 88: 1286-1291; Brown A K, Christo PJ, Wu CL. Strategies for postoperative pain management Best Pract Res Clin Anaesthesiol. 2004; 18: 703-717.

A recent phase 2 study characterized the safety and efficacy of controlled release hydrocodone and acetaminophen (HC / APA P CR) in patients with acute pain after bunionectomy surgery and found that 1 and 2 tablets twice daily of HC / APAP CR were significantly superior to placebo (P¡ = .05) in reducing pain intensity and in providing the iv of adequate pain after a single dose of the drug provided within 6 hours after surgery. Desjardins P, Diamond E, Francis C, and others. Pain treatment with controlled-release hydrocodone / acetaminophen tablets 12 hours after acute bunionectomy: a randomized, double-blind, placebo-controlled study presented at the American Academy of Pain Medicine. New Orleans, Luciana; 2007 Post-bunionectomy pain is considered a robust and reliable acute pain model to assess analgesic efficiency with multiple doses, 6 and is associated with a predictable level of moderate to severe post-operative pain. Desjardins PJ, Black PM, Daniels S, and others. A randomized controlled study comprising rofecoxib, diclofenac sodium, and placebo in post-bunionectomy pain. Curr Med Res Opin. 2004; 20: 1523-1537.

Methods: 163 patients recruited from 5 sites of E. U.A. for the following treatment groups: 2 placebo tablets (n = 53), one HC / APAP CR tablet plus placebo (n = 54), or 2 HC / APAP CR tablets (n = 56) at the onset of moderate pain to severe. Patients were dosed every 12 hours for 481 hours (4 total doses), and after the first dose, was followed for 7 days [± 2]. The primary end point was the compensated sum of pain intensity difference time interval (SPID) in the first 12 hours, as measured by visual analogue scale (VAS), (upper marks indicate better pain relief). Patients received rescue medication as necessary.

Specifically, this randomized, multiple-center, double-blind, placebo-controlled controlled study evaluated the efficacy and safety of 15 mg / 500 mg of HC / APAP CR, 2 tablets twice daily, in patients with moderate pain. severe after bunionectomy surgery. The study was conducted from January 2007 to April 2007. A total of 163 patients recruited from 5 sites of E. U.A. for the following treatment groups at the beginning of moderate to severe pain: 2 placebo tablets (n = 53), one HC / APAP CR tablet plus placebo (n = 54), or 2 HC / APAP CR tablets (n = 56) Patients were dosed every 12 hours for 48 hours (4 total doses), and continued until study day 7 [± 2 days] then read the first dose of study medication. The duration of the study was approximately 4 weeks (Figure 15).

Main inclusion criteria Eligible participants were between 1 8 and 65 years of age, and were in good general health.

The patients were scheduled to undergo primary unilateral, first metatarsal bunionectomy surgery under anesthesia and regional / local sedation. Patients reported a pain intensity mark of > 40 mm on one scale: visual analogue of 100 mm (VAS, 0 = no pain, 100 = unimaginable pain) and had a moderate to severe pain score on a categorical pain intensity scale in the morning after surgery.

Statistic analysis All analyzes were conducted using the intention-to-treat (ITT) data set that included all patients who received at least one dose of study drug. For all endpoint points of efficacy and safety, the primary comparisons were between the group treated with 2 tablets of HC / A PA P C R 2 and the g roup treated with placebo. The mean differences of the treatment group for the primary efficacy variable were evaluated when using ANCOVA with factors for the treatment group, researcher, VAS pain intensity marker of the baseline as a covariate juna.

The time for the release of noticeable, significant and confirmed pain from the patient was analyzed by using non-parametric survival model registration range statistics and Wald statistics of Cox proportional hazard models (with Kaplan-Meier estimates). average time to start or first use) For the primary efficacy analysis, all data obtained after subjects received any rescue medication were excluded from the analysis. The missing / excluded pain marks were imputed by using the latest observation transported management methodology (LOCF).

Efficiency and safety results The primary endpoint was the compensated sum of the pain intensity difference time interval (SPI D) in the range of 0-12 hours after study drug administration, as measured by VAS (upper marks indicate greater improvement in the intensity of pain from the baseline).

Secondary end points were the time for the pain release, noticeable, significant, and confirmed! of the patient measured in minutes.

Safety was assessed through the study by physical examinations, viral signs, laboratory tests, and monitoring of adverse events (AEs).

Results: 161/163 patients completed the study. | The baseline variables were similar between the groups. The majority of patients were women (89%); the average age was 42. 1 years. Patients who received HC / APAP CR showed statistically significant improvement in all the efficacy variables reported here, except one HC / APAP CR tablet for perceptible pain relief (Table 1 1 A).

Table 1 1 A. Effectiveness results for 0 to 1 2 hours Variables Placebo 1 tablet of 2 tablets (n = 53) HC / APAP CR HC / APAP CR (n = 54) (n = S6) SPI D VAS, relief of 35.8 21 1 .8 (32.2) to 367.3 (31 .6) average pain (SE), (32.5) n (%) Perceptible 42 (79) 47 (87) 55 (98) at t > Significant 27 (51) 41 (76) to 53 (95) to D Perceptible confirmed 27 (51) 40 (74) to 52 (93) to D 3 p < 0.05 against placebo b p < 0.05 against 1 tablet The incidence of adverse events was significantly higher for patients receiving HC / APAP CR versus placebo and for patients receiving 2 tablets of HC / A PAP CR against one tablet. The most common adverse events were nausea, vomiting, drowsiness, headache, dizziness, and pruritus.

Specifically, a total of 163 patients received at least one dose of study drugs and were included in the ITT analysis (n = 53 placebo, n = 54 HC / APAP CR one tablet, n = 56 HC / A PA PCR 2 tablets) . The baseline demography was comparable among the 3 treatment groups by age, race, weight, and height. There was a statistically significantly different proportion of men and women among the 3 treatment groups. The majority of patients were white (80% and women (88%, and the average age was 42.1 years (Table 11).) Table 1 1 illustrates the demographics and baseline characteristics.

Effectiveness Primary end point The average VAS SPID scores for 0 to 12 hours after the initial dose for the groups treated with 1 and 2 HC / APAP CR tablets were significantly higher compared to the placebo group (p <.001; Figure 2) , which indicates a greater improvement in pain intensity from the baseline.

The mean SPAS VAS scores for the group treated with 2 HC / APAP CR tablets were significantly matched compared to the group treated with a HC / APAP CR tablet (p = .001; Figure 16).

Secondary endpoints The times for the onset of significant and confirmed pain relief were significantly lower in the groups treated with 1 and 2 HC / APAP CR tablets compared with the placebo group (P = .05; Table 3).

A significant difference was also observed between the group treated with 2 HC / APAP CR tablets and the placebo group at the time of noticeable pain relief (P = 05, Table 3) Significantly shorter times were observed for pain relief perceptible, significant, and confirmed in the group treated with 2 tablets of HC / APAP CR compared to the group treated with a HC / APAP CR tablet (P <05; Table 1s |). Table 13 illustrates at the time for pain relief.

Severe reports were reported by 26% of patients in the group treated with 2 HC / APAP CR tablets, 28% of patients in the group treated with a HC / APAP tablet, and 10% of patients in the treated group with placebo.

There were no deaths during the study. Two patients experienced serious AE (SAE); both were hospitalized for thromboembolic events considered secondary to post-operative immobility. One patient in the HC / A PA P CR group experienced deep vein thrombosis, and a second patient in the 2-tablet group experienced a pulmonary embolism. No SAE was considered possible or probably related to the study drug.

Valuations of clinical laboratory and signs vitaiejs were not remarkable for all treatment groups.

Conclusion: 1 or 2 tablets of HC / APAP CR provided significantly better pain relief when compared to placebo in patients with moderate to severe acute pain after this bunion action. Two tablets provided consistently superior pain relief when compared to 1 tablet. The safety data demonstrated an AE profile consistent with that of an agent containing mu opioid receptor.

Example XI Acute pain treatment with 12-hour extended release hydrocodone / acetaminophen tablets after bunionectomy The safety and efficacy of 15 mg hydrocodone / 500 mg acetaminophen (HC / APAP CR) extended release dosed every 12 hours and 10 mg hydrocodone / 325 mg short acting acetaminophen (HC / APAP IR) dosed every 4 hours they were compared with placebo for moderate to severe pain on the day after primary unilateral bunionectomy of the first metatarsal.

Methods: Patients were randomly selected for a dose of 2 tablets of HC / APAP CR (n = 26), or 1 tablet of HC / A PAP I R. (n = 31) every 4 hours for 3 doses, or placebo ( n = 31) and were evaluated for 12 hours. The primary endpoint was the compensated sum of time interval of pain intensity difference (SPI D) for 0-12 hours after the initial drug administration when using 100 mm of VAS. Secondary end points included categorical SPID scale of pain (0-12 hours), intensity difference (PID), compensated sum of time interval of pain relief (TOTPAR, 0-12 hours) and pain relief and difference of inteid of pain (SPRI D). The safety assessment included reports of adverse event (AE).

Results: The baseline characteristics were similar among the treatment groups. The average SP I D scores (0-1 2 hours) were statistically higher for HC / APA P C R (333) and HC / A PAP I R (242) versus placebo (20.7). The categorical scores of SPI D and average TOTPAR for HC / APA P treatment groups were statistically significantly higher compared to the placebo treatment group. Starting at the 1-hour post-dose, the average PI D scores for the HC / APAP C R group were statistically significantly higher than placebo and numerically higher than the HC / A PA P I R group for all subsequent assessments. At 5 hours, the HC / A PAP CR group had significantly higher PID than the HC / APAP I R group. There were no significant differences between each of the HC / APAP treatment groups and placebo in the proportion of patients who experience AE. The emerging treatment AEs experienced by >5% in the HC / APA P treatment group were nausea, vomiting, headache, dizziness, somnolence, fatigue, and hypotension. Nausea was the most frequently reported AE and was reported by a statistically significantly higher proportion of patients in the HC / APAP I R treatment group compared with placebo. No i A E Iserio was reported during the study.

Conclusions: For postoperative pain, HC / APAP G R and HC / A PA P I R were significantly superior to placebo in providing effective pain relief. The rates of adverse events with each one were not statistically significantly higher than placebo and were consistent with those of a mu opioid analgesic.

Example XI I Effects of 12-hour extended-release hydrocodone / acetaminophen treatment on cytochrome deficient metabolizers P450 2D6 Hydrocodone is oxidized to a mu opioid agonist hydromorphone by cytochrome P450 2D6 (CYP2D6). Deficient metabicylates of CYP2D6 (PM) do not convert hydrocodone to hydromorphone, and it is believed that PM.no will not have significant analgesia of hydrocodone. The PM responses were compared with those of competent metabolisers (non-PM) during extended release treatment of hydrocodone / acetaminophen (HC / APA PCR) after bunionectomy surgery and in osteoarthritis patients, to learn if PM of CYP2D6 can treat effectively with HC / APAP CR. DNA samples collected from patients enrolled in two multi-site placebo-controlled clinical trials were classified by genotype for major CYP2 D6 PM alleles and assigned PM or non-PM status. In an acute pain ivio study after bunion surgery, the efficacy variables were evaluated disparagingly. In a study of chronic pain in osteoarthritis, the efficacy of the HC / APAP CR treatment was evaluated possibly for the percentage change from the baseline to the 12th week of pain intensity mark (percentage of VAS), when using analysis of covariate with a factor for PM status and baseline pain intensity mark as a covariate. Other end points of effectiveness were evaluated to support the probable analysis. Tolerability HC / A PAP CR in PM was descriptively assessed in both studies. Among 1 30 subjects with bunionectomy, 4 of 6 PM dosed with H C / A PA P l C R experienced significant analgesia. Among 276 subjects l with osteoarthritis, 1 1 of 19 PM dosed with HC / APAP | CR experienced significant analgesia. No difference was observed between PM and non-PM for VAS% (-43.5% v -46.5%, p = 0.770). The PM treated with placebo (-21.0%, n = 19) | they also did not respond to HCs treated with HC / APAP: CR The results for other key efficacy variables were consistent with those for% of VAS. The safety-related study drop and adverse event patterns were similar in PM and non-PM in both studies. PM and non-PM had similar analgesic responses to HC / APAP CR this distinguishes HC / A PA C R from tramadol and possibly from other opioid-based analgesics.

Example XIII Efficacy and safety evaluation of hydrocodone / acetaminophen treatment with 12-hour extended release in patients with chronic low back pain (CLBP) due to previous opioid use 15 mg hydrocodone / 500 mg acetaminophen extended release 12 hours twice daily (HC / APAP CR) demonstrated superior efficacy compared to placebo for the treatment of moderate to severe chronic low back pain (CLBP) in a test of previously reported abstinence chosen at random from 12 weeks, with double blind, placebo controlled. This report evaluates the efficacy and safety of HC / APAP CR for the use of prior opioid.

Methods: Patients who already experienced opioid (took opioids for CLBP in the last month, 302 of 770 (39%) and patients who have not experimented with opioids (did not use opioids in the last time, 468 of 770 (61 %) with CLBP were controlled in 62 sites of E. U.A. The study periods were: washing / monitoring, open label of active drug of 3 weeks (OL), double blind (DB) of 12 weeks where patients were randomly selected for placebo, 1 or 2 tablets of HC / APAP CR twice a day, and reduction / follow-up.The end point of primary efficacy was the average change from the DB baseline to the evaluation end in the CLBP intensity assessment of the subject (visual analog scale, 0-100). Safety was evaluated for the adverse event (AE), and the vital sign and laboratory assessment.

Results: 209/302 (69%) of patients who experienced opioids and 302/468 (65%) of those who did not experience opioids complemented the OL period and were randomly selected in the DB period. For the primary endpoint, both the groups of experienced and non-opioid patients received HC / APAP CR that had lower average increases from the DB baseline compared with placebo; this difference was statistically significant for groups of 2 tablets (p <0.03). There were no statistically significant differences (p = 0.467) for the primary endpoint between patients who experienced and who did not experience opioids receiving placebo, 1 tablet of HC / A PA P CR or 2 tablets of HC / APAP CR. There were no significant differences (p> 0.05) in overall adverse event rates across treatment groups for patients who experienced opioids i [placebo (51%), one HC / APAP CR tablet (43%) or 2 tablets of HC / A PA P CR (52%)] or who did not experience opioids [placebo (42%), one HC / APAP CR tablet (45%) or 2 HC / APAF tablets? CR (53%)].

Conclusions: In this study, HC / APAP CR was effective | for the treatment of moderate to severe CLBP and the efficacy and safety profiles were similar for patients who experienced and who did not experience opioids.

Example XIV Safety and tolerability of long-term extended release hydrocodone / acetaminophen in patients with moderate to severe non-cancer pain from prior opioid use 15 mg of hydrocodone / 500 mg of acetaminophen from the extended release of 12 hours twice a day (H C / APA P C R) showed efficacy for the treatment of moderate non-cancer pain! to severe in a long-term open label study (56 weeks) previously reported. This report evaluates the safety and efficacy of HC / APAP CR for the use of patients' previous opioids.

Methods: 431 patients with moderate to severe non-cancer pain (osteoarthritis / OA or chronic low back pain / CLBP) were recruited from 74 sites of E.U.A. In the titration period, patients take a HC / APAP CR tablet once a day for 3 days followed by a tablet twice a day for 4 days. During maintenance, patients take 2 tablets of H C / A PA P CR twice a day for 56 weeks. After the maintenance period, the periods had their medication reduced by 1 week. Patients were allowed to take rescue medication (acetaminophen) up to 3 times per week. Safety was assessed for the adverse event (AE), vital sign and laboratory assessment and efficacy was assessed by a pain intensity scale of 1 1 points.

Results: 291 of the 431 (68%) patients who entered the study experienced opioids (they took opioids in the last month to treat OA or CLBP) and 140 (32%) did not experience opioids. The overall AE rates were significantly higher in patients who did not experience opioids (92%) compared to patients who experienced opioids (83%, p = 0.012) and the most common AEs were nausea (39% and 19% for patients who experienced and that they did not experience, respectively) and dizziness (11% and 5%). A higher percentage of patients who did not experience opioids discontinued the study mainly due to AE (32%) compared to patients who experienced opioids (23%). In the final evaluation, the group of patients who did not experience opioids had percentage improvements mean scores in pain intensity from the baseline (-33.8) compared to the group of patients who experienced | with opioids (-29.7); These differences were not statistically significant (p = 0.435).

CONCLUSIONS: In the long-term study, the AE indices were significantly higher in the group that did not experience opioids compared to the group that experimented with opioids and the similar efficacy was observed for patients who experienced and who did not experience opioids. receive HC / APAP CR.

Example XV HC / APAP CR Tablets have greater compressive strength than six other opioid formulations The objective was to determine whether the extended-release tablets of 15 mg hydrocodone / 500 mg of acetaminophen (HC / APAP CR) had a resistance significantly different to the compression strength than the tablets of inmédial liberation to 5 mg / 325 mg hydrocodone / acetaminophen (HC / APAP IR) and controlled release tabals of 10 mg / 325 mg of HC / APA PIR, 1 0 mgy and 80 mg of oxycodone HCI (O / HCI CR), and liben tablets. 5 mg and 40 mg of oxymorphone hydrochloride (OPANA ER).

Methods: Individual tablets were individually compressed or sliced into a plate dam that can be adjusted with one of four different devices: a 4 mm Indian plate, a plate shaped like a human incisor, a plate shaped like a human mole, and a blade with individual edges. The pressure of all the devices was set at 0.3 mm / second, which is approximated at a slow chewing speed. For HC / APAP CR, the force (N) needed to fracture (1) the outer sheath only and (2) the core tablet alone was recorded. For all the other tablets, only registered. the force required to fracture the core tablet. The tablets were tested as well as "in the current state" (directly from the bottle) and then the tablets were pre-soaked for 2 minutes in approximately 1 ml of artificial saliva (dry mouth humectant oral balance of Biotene, Laclede , Inc.). The results were recorded as kilo Newtons (kN) and relative standard deviations (RSD) expressed as a percentage. Each test condition was repeated 6 times for each drug so that statistical inferences could be drawn.

Results: All the comparison products were considered not to be statistically similar to H C / A PAP C R in resistance to compression force. The order of classification of the strength of the breaking force for the product! tested i "in the current state" was HC / APAP CR > O / HCI CR 80 mg > Ó / H CI C R 10 mg ~ 5/325 HC / APAP I R ~ 10/325 HC / APAP I R ~ OPA NA ER mg ~ OPANA ER 40 mg. A similar trend was observed for | tablets after pre-soaking for 2 minutes in artificial saliva. In addition, the force required to fracture the outer lining of the HC / APAP CR tablets was greater than the required strength to fracture the comparator tablets.

Conclusions: HC / A PAP CR tablets required significantly more compression strength statistically than tablets of 5/325 mg and 10/325 mg of HC / APAP IR, 10 mg j and 80 mg of O / HCI CR, and 5 mg and 40 mg of OPANA ER.

Example XVI Safety and tolerability of long-term extended-release hydrocodone / acetaminophen in patients with non-moderate to severe pain from previous opioid use 15 mg of hydrocodone / 500 mg of extended release acetaminophen 12 hours twice daily (HC / APAP CR) showed efficacy for the treatment of pain not of moderate to severe cancer in a long-term open label study previarr reported entity (56 weeks). This report evaluates the safety and efficacy of HC / APAP CR for previous opioid use of patients.

Methods: We enrolled 431 patients with moderate to severe non-cancer pain (osteoarthritis [OA] or chronic low back pain [CLBP]) from 74 sites of E. U.A. In the titration period, patients take a HC / APAP CR tablet once a day for 3 days followed by 1 tablet twice a day for 4 days. During maintenance, patients take 2 HC / APAP CR tablets twice a day for 56 weeks. After the maintenance period, patients had their medicine reduced by 1 week. Patients were allowed to have rescue medication (acetaminophen) up to 3 times per week. Safety was assessed for the adverse event (AE), vital sign, and laboratory assessment and effectiveness was assessed by a pain intensity scale of 1 1 points.

Results: 140 of the 431 (32%) patients who entered the study did not experience opioids and 291 (68%) experimented with opioids (they took opioids in the last month to treat OA or CLBP). Overall AE rates were significantly higher in patients who did not experience opioids (92%) compared to patients who experienced opioids (83%, p = 0.012) and the most common AEs were nausea (39% and 19%). for patients who experienced and who did not experience, respectively) and dizziness (11% and 5%, respectively). A greater percentage of patients who did not experience opioids discontinued the study mainly due to AE (32% compared to patients who experimented with opioids (23%).) In the final evaluation, the group of patients who did not experience opioids had greater improvements of average percentage in pain intensity from baseline (-33.8) compared to the group of patients who experimented with opioids (-29.7), these differences were not statistically significant (p = 0.435).

Conclusions: In this long-term study, the AE rates were significantly higher in the group that did not experience opioids compared to the group that experimented with opioids and similar efficacy was observed for patients who experienced and who did not experience opioids receiving HC / APAP CR.

Osteoarthritis (OA) and chronic low back pain (C L B P) are 2 of the most prevalent types of chronic non-cancer pain syndromes in the U.A. 1, 2 acetaminophen (APAP) and non-spheroidal anti-inflammatory drugs (NSAIDs) continue to be the first-line pharmacological therapies used to tighten pain syndromes other than cancer, such as OA and C LBP. For patients with OA and CLBP whose pain is not effectively managed by APAP or NSAID, combination opioids (containing codeine, hydrocodone [HC], or oxycodone) may be important treatment alternatives. 3 combination opioids, including HC / APAP, proved to be effective in the treatment of moderate to severe pain syndromes, such as OA and CLBP, but are currently available only in short-acting formulations.

The extended-release formulation can potentially increase patient compliance, reduce the frequency of end-of-dose pain, and improve the overall quality of life of individuals with moderate or severe chronic non-cancer pain syndromes.

The results of a long-term open label study demonstrating the safety and tolerability of 56 weeks of HC / APAP extended-release (HC / APAP CR) in the treatment of non-chronic cancer pain in 431 patients with OA and CLBP were previously reported. Opioids were shown to be generally effective in populations that experienced no They experimented with opioids. 5-7 patients who experienced! with opioids are considered more able to tolerate opioids than patients who did not experience opioids. In clinical trials, patients who did not experience opioids generally have higher fall rates due to adverse events (AE) than patients who experienced opioids. Slow titration is often considered useful in mitigating these side effects. 8 In this study, an analysis of its post hoc, explanatory bg rupo was conducted to determine whether the safety and tolerability trends of the long-term treatment of non-chronic cancer pain observed in a 56-week multiple center study Recent studies were preserved when the study population was stratified by the history of opioid use.

Methods: study design This open-label, multi-center study was designed to assess the safety and tolerability of HC / A PA P CR tablets of 15 mg / 500 mg for 12 hours administered twice daily in patients with moderate chronic non-malignant pain. Severe exemplified by OA pain of the hip or knee, or CLBP. (Figure 17). This study was conducted from July 2005 until December 2006. 431 patients enrolled in 74 study sites. Patients eligible for inclusion in this analysis had; between 21 and 75 years of age; met the ACR criteria for OA of the hip or knee or experienced mechanical lower back pain under the twelfth thoracic vertebra for no more than 3 months; they took an analgesic for OA or CLBP for most of the days in the previous 3 months and at least 4 days / week during the 4 previous weeks before the monitoring; and they had a rating of the subject's pain intensity scale of = 4 at the baseline (0 = no pain, 1 0 = create pain imaginable). Patients should be an appropriate candidate for opioids throughout the day as their next step in analgesic administration by meeting at least one of the following criteria: require an opioid (< 40 mg / day oral morphine equivalent, including the advancing pain medication), or were unable to control pain with non-opioid analgesics, or such analgesics were contraindicated. Patients who meet the selection criteria will enter the washout period, and the use of prior analgesic was discontinued for 5 half-lives or 2 days, whichever is longer. Patients returned to the study site and enrolled in a 7-day titration period (with an optional second week of titration) if they met the eligibility criteria, including a brand of > 4 (out of 10) in the subject's pain intensity scale. During the titration period, patients take a HC / A PA P C R tablet once a day for 3 days, followed by a HC / APAP CR tablet twice a day for 4 days. After the titration period, patients returned to the study site and entered the maintenance period, during which they took 2 HC / APAP CR tablets twice a day for 56 weeks.

After the maintenance period, patients were admitted to the one-week study drug reduction period, during which patients received a HC / APAP CR tablet twice daily for 4 days, followed by a tablet once a day. a < for 3 additional days, after which HC / APAP CR is discontinued. (Figure 17). A follow-up visit was conducted 1 week after discontinuation of study drug.

Rescue medication was not allowed within 24 hours prior to the baseline visit or scheduled study visits; however, patients were allowed to take APAP as rescue medication (not to exceed 2000 mg / day) during the periods of washing, titration, maintenance and reduction of the study. All use of APAP was recorded in the patient's diary. During the titling and maintenance, the rescue was limited to 3 days per week. The post-hoc analyzes that control the history of opioid use were made. All demographic and safety analyzes were performed using an attempt to treat (ITT) data set. All enrollees who received one i2 s of study drug were included in the ITT analyzes. The evaluation data of efficacy excluded the 16 patients from a single study center because some patients were verbally aided by study center personnel in the translation of some portions of the efficacy assessment questionnaires. Patients were appointed to see or not experienced opioids when answering no or yes to the following Question: "Did the subject previously receive opioid therapy to treat their OA pain or lower back pain?" Results of safety and efficacy Safety was verified through the study based on assessments of adverse events (AE), physical exams, vital signs and laboratory tests.

The AEs were coded by using the medical dictionary [for normative activities (MedDRA) and emergency treatment AE was tabulated by the organ system class (SOC) and MedDRA's preferred term. Efficacy was assessed by pain intensity on a Likert scale of 1 1 points (0 = painless, 10 = worst imaginable pain).

Baseline demography A total of 140 (32%) patients who entered the study did not experience opioids and 291 of the 431 (68%) experienced opioids. (Picture 15). Table 15 illustrates the demographic and baseline characteristics of opioid use.

In the general population, twenty-five (6%) patients reported one or more AE (SAE), none of which was considered by the researcher to be possible or probably related to the study drug. No clinically important trends were observed in serious adverse events within or in 3 subgroups of opioid use history. The differences in serious adverse events (SAEs) analyzed by opioid use history were not statistically significant (p = 0.509). A total of 10 out of 140 (7%) of patients who did not experience opioids and 1 5 out of 291 (5%) of patients who experienced opioids had at least one SA E.

Effectiveness Many reductions in the valuation were observed! of the pain intensity mark patient from the baseline and initiating the first evaluation (week 4) and continuing to read the scheduled evaluation through the study. In the final evaluation, the group of patients who did not experiment with opioids had higher mean percentage improvements in pain intensity from the baseline (-33.8%) compared with the group of patients who experimented with opioids (-29.7% ); these differences were not statistically significant (p = 0.435). In all but one visit, there were no statistically significant differences in efficacy between patients who did not experience and who experienced opioids (Figure 18). Figure 18 illustrates average reductions in patient valuation of pain intensity score from the baseline (observed cases: evaluable efficacy set).

The overall results of this first study examining the long-term safety and tolerability of HC / APAP CR indicate that: the HC / APAP CR safety profile in this study was consistent with that of an agent containing acetam irioferji agonist opioid receptor.

HC / A PAP CR was effective in the management of moderate to severe chronic pain in a period of 56 weeks. When safety and efficacy are evaluated by history of opioid use. The number of patients reporting at least one adverse event (particularly nausea and dizziness) was statistically significantly higher in patients who did not experience opioids compared to patients who experienced opioids. Overall premature discontinuation rates were similar among patients who did not experience and who experienced opioids, but the rates of premature gene discontinuation due to adverse events were statistically significantly higher in patients who did not experience opioids compared to patients who experienced opioids. with opioids Similar efficacy was observed for patients who did not experience and who experienced opioids with severe chronic non-malignant pain receiving HC / APAP CR over a period of 56 weeks.

The present invention generally provides a method of treatment and improvement of quality of life for patients adversely affected by various pain conditions. A preferred embodiment provides a method of treating acute pain, moderate to moderately severe pain, chronic pain, non-cancer pain, osteoarthritic pain, bunionectomy pain or lower back pain in a patient in need, comprising providing at least one or two dosage forms which have about 15 mg of hydrocodone and its salt and about 500 mg of acetaminophen, once, twice or three times a day. Preferably, the dosage form is about 30 mg of hydrocodone and about 1000 mg of acetaminophen taken twice a day. Alternatively, the dosage form is about 15 mg of hydrocodone and about 500 mg of acetaminophen taken twice a day. As well, preferably, these dosage forms can be taken by the patient with or without n food. In another aspect of the invention, the co-administration of approximately 240 ml of 40%, 20%, 4% and 0% ethanol in the single dose form affects the maximum plasma concentration level Cmax average by = 25% both for hydrocodone and for acetaminophen in the patient. In another aspect, Cmax and AUD of hydrocodone for a patient with mild to moderately impaired hepatic function is substantially similar to the normal patient and Cm ax and AUC of acetaminophen for a patient with slightly impaired hepatic function is substantially similar to the patient. normal patient. Also, no general statistical differences in effectiveness were observed for the patient metabolize hydrocodone when the patient is a deficient or competent metabolite of Cytochrome P450 2 D6 polymorphism Another embodiment of the invention provides a method for improving the quality of life in a patient in need thereof, which comprises administering to said patient a dosage form twice a day of controlled release that includes acetaminophen and hydrocodone or a therapeutically effective salt. of the masters. In use in another embodiment, the invention provides a method for reducing the loss of productivity in a patient having a pain-related condition, which comprises administering to the patient a dosage form twice a day of controlled release including acetaminophen. and hydrocodone or a therapeutically effective salt thereof. Preferably, the dosage form comprises about 15 mg of hydrocodone or a therapeutically acceptable salt thereof and about 500 mg of acetaminophen. Or preferably, in all the above embodiments, the dosage form comprises about 15 mg of hydrocodone or a therapeutically acceptable salt thereof and about 500 mg of acetaminophen. Alternatively, the dosage form comprises approximately 30 mg of hydrocodone or a therapeutically acceptable salt thereof and approximately 1000 mg of acetaminophen.

The illustrative embodiments described above are intended to be illustrative in all respects, rather than restrictive, of the present invention. Thus, the present invention is capable of impiementation in many variations and modifications that can be derived from the description herein by one skilled in the art. All such variations and modifications are considered to be within the scope and spirit of the present invention as defined by the following claims.

Claims (12)

1 .- A method of treatment of acute pain, moderate to moderately severe pain, chronic pain, non-cancer pain, osteoarthritic pain, bunionectomy pain or lower back pain in a patient who needs the same comprises providing at least one or two dosage forms comprising about 15 mg of hydrocodone and its salt and about 500 mg of acetaminophen, once, twice or three times a day.

2. - The method according to claim 1, wherein the dosage form is about 30 mg of hydrocodo na and about 1000 mg of acetaminophen taken twice a day.

3. - The method according to claim 1, wherein the dosage form is about 15 mg of hydrocodone and about 500 mg of acetaminophen taken twice per day.

4 - . 4 - The method according to claim 1, wherein said dosage form can be taken by the patient with q if n food.

5. - The method according to claim 1, wherein the co-administration of approximately 240 ml of 40%, 20%, 4% and 0% ethanol in the single dose form affects the level of concentration in average maximum plasma Cmax for < 25% for both hydrocodone and acetaminophen in the patient.

6 -. 6 - The method according to claim 1, wherein the C max and AUC of hydrocodone for a patient with mild to moderately impaired hepatic function is substantially similar to the normal patient and wherein the Cm ax and AUC of acetaminophen parch a patient with moderately impaired liver function I is substantially similar to the normal patient.

7. - The method according to claim 1, wherein no general statistical differences in effectiveness were observed for the patient metabolizing hydrocodone when the patient is a deficient or competent metabolizer of polymorphism! of Cytochrome P450 2D6.

8. A method for improving the quality of life in a patient in need, which comprises administering to said patient a dosage form twice a day of controlled release including acetaminophen and hydrocodone or a therapeutically effective salt thereof.

9. A method for reducing the loss of productivity in a patient having a pain-related condition, which comprises administering to the patient a dosage form twice a day of controlled release that includes acetaminophen and hydrocodone or a therapeutically effective salt thereof.

10. The method according to any of claims 8 and 9, wherein the dosage form comprises about 15 mg of hydrocodone or a therapeutically acceptable salt thereof and about 500 mg of acetaminophen.

The method according to any one of claims 1, 4, 5, 6, 7, 8 and 9, wherein the dosage form comprises approximately 15 mg of hydrocodone or one | therapeutically acceptable salt thereof and about 500 mg of acetaminophen.

12. - The method according to any of | claims 1, 4, 5, 6, 7, 8 and 9, wherein the dosage form comprises about 30 mg of hydrocodone or a therapeutically acceptable salt thereof and about 1000 mg of acetaminophen. SUMMARY The present invention generally provides a method of treatment and improvement of quality of life for patients adversely affected by various pain conditions. A preferred embodiment provides a method of treating acute pain, moderate to moderately severe pain, chronic pain, non-cancer pain, osteoarthritic pain, bunionectomy pain or low back pain in a patient with the need thereof. it comprises providing at least one or two dosage forms having about 15 mg of hydrocodone and its salt and about 500 mg of acetaminophen, once, twice or three times a day. Preferably, the dosage form is about 30 mg of hydrocodone and about 1000 mg of acetaminophen taken twice a day. Alternatively, the two-s form is about 15 mg of hydrocodone and about 500 mg of acetaminophen taken twice a day.