(757): Morphine release profile in a formulation containing polymer-coated extended-release morphine...

(756) Case-control study on risk factors for prescription opi-oid abuse among patients with pain

C Bieber, H Thomson, D Borsook, M Brennan, S Butler, K Fernandez, R Jamison,E Osgood, J Sharpe Potter, R Weiss, N Katz; Inflexxion, Needham, MAWhile opioid analgesics have been shown to be effective in the treat-ment of chronic pain, they are also associated with risk of addiction.Little is known about what significance a patient’s initial experiencewith opioid medications may have in predicting future development ofaddiction. This case-control study proposes to generate hypotheses toidentify risk factors at the time of initial exposure to opioids for pain.Cases were individuals in an inpatient substance abuse treatment centerfor primary prescription opioid abuse. Controls, individuals who wereusing prescribed opioids for at least 3 months who had not developedaddiction, were from a pain management center. Subjects completed anumber of measures to capture data from the individual’s first exposureto prescription opioids. Between-group differences on the instrumentsas well as on the individual items were compared using t-tests for con-tinuous variables and Fisher’s exact test for categorical variables. TheARCI, designed to measure euphoria and other drug effects, showed themost significant between-group difference. Those items significant formorphine showed a difference between means of 5.68 (95% CI3.58,7.78) with a t-value of 5.31 (p-value �.0001) Item analysis of theARCI showed significant differences (cases 81%, controls 0) betweengroups: “A thrill had gone through me” and “I feared I would lose thecontentment that I had then.” Euphoria and other differences in thesubjective response to opioids suggest the hypotheses that (1) a sub-group of patients with pain does develop euphoria when taking opioidsfor pain, and (2) this experience of euphoria may be a risk factor for theeventual development of prescription opioid addiction.

(757) Morphine release profile in a formulation containingpolymer-coated extended-release morphine sulfateplus sequestered naltrexone

F Johnson, S Sun, J Stauffer, G Wagner; Cedra Corporation, Austin, TXFear of government action against healthcare providers who prescribeopioids is a contributing factor to the under-treatment of chronic pain.1

There is a demand for products with reduced abuse liability.2 One suchformulation under development includes polymer-coated extended-re-lease morphine sulfate (P-ERMS) surrounding a sequestered core of nal-trexone, an opioid antagonist that competes at the opioid receptor sites.The product is designed to release naltrexone if product tamperingoccurs by crushing, chewing, or dissolving. Morphine pharmacokineticsof this formulation were assessed in this single-dose, open-label, two-period crossover study (fasted and fed) in eight healthy subjects aged 21to 45 years. After an overnight fast, subjects either received study drug(containing 60-mg morphine sulfate) or consumed a standard high-cal-orie, high-fat breakfast and took the dose 30 minutes later. Blood sam-ples for morphine pharmacokinetic analysis were drawn prior to dosingand at intervals from 0.5 to 168.0 hours postdose. For the 60-mg mor-phine dose, Cmax was 10.70 ng/mL fasted and 9.18 ng/mL fed. AUCinf was260.6 hr*ng/mL fasted and 246.0 hr*ng/mL fed. The Tmax for morphinewas 7.50 hours fasted and 8.75 hours fed, consistent with a sustained-release profile and with current prescribing information for P-ERMS.3

Adverse events, reported in five subjects, were either mild or moderatein intensity, and resolved. Study results demonstrated that the releasecharacteristics of morphine in this formulation containing a sequesterednaltrexone core were similar to characteristics demonstrated in previousstudies of P-ERMS. The study formulation was well tolerated. (1. Jung,Pain Med, 2006; 2. Wright, Drug Alcohol Depend, 2006; 3. KADIAN®

package insert, Alpharma Branded Products).

(758) In vivo pharmacokinetics of KADIAN® (morphine sul-fate extended-release) capsules taken with alcohol

S Sun, F Johnson, J Stauffer, G Wagner; MDS Pharma Services, King of Prussia,PAIn 2005, PalladoneTM (hydromorphone hydrochloride extended-releasecapsules) was removed from the market due to pharmacokinetic dataindicating that ingestion with 240mL of 40% alcohol resulted in averagepeak hydromorphone concentrations approximately 6 times greaterthan when taken with water.1 This has prompted studies of the interac-tions of other extended-release products with alcohol. This open-label,randomized, single-dose, 3-way crossover study assessed single-dose rel-ative bioavailability of KADIAN® (morphine sulfate extended-release)Capsules taken with alcohol vs water. Thirty-two opioid-naı̈ve, healthymale volunteers, aged 21-40y, who were moderate drinkers (7-21 drinks/week) took a 100mg KADIAN® Capsule with 240mL of 40% alcohol (4shots [101mL] 190-proof Everclear®, 139mL water, consumed within20min of dosing) fasted and fed, and with 240mL of water (fasted) as areference. Open-label arm of immediate-release 20mg morphine solu-tion was included for comparison. Oral naltrexone hydrochloride, anopioid antagonist, was administered 12h and 2h prior to treatment tocounter morphine effects. Twenty-seven subjects had evaluable phar-macokinetic data for �1 treatment arm. Eleven subjects vomited aftertaking KADIAN®�alcohol; none vomited after taking KADIAN®�water.Median time to maximum morphine concentration (Tmax) in subjectstaking KADIAN® with alcohol fasted, with alcohol fed, and with waterfasted was 8.0, 8.0, and 8.0 h, respectively, consistent with maintenanceof a sustained-release profile. Excluding patients who vomited duringthe 12h dosing interval,2 maximum morphine concentrations (Cmax;mean of log-transformed values) were similar in all 3 groups: 16.7, 16.0,and 15.6ng/mL. ANOVA showed ratios of least square means for Cmaxand overall morphine exposure (AUC) of both regimens ofKADIAN®�alcohol within 80%-125% confidence interval boundarieswhen compared with KADIAN®�water. In contrast, the pharmacoki-netic profile of 20mg solution was markedly different from the testtreatments. Results indicate that KADIAN® taken with 240mL of 40%alcohol continued to display extended-release characteristics. (1. FDA,2005; 2. FDA, 2003).

D15 - Opioids in Non-Cancer Pain(759) Attenuation of mechanical allodynia with peripherally

acting mu-opioid receptor agonist in rat after L5 spinalnerve injury

Y Guan, L Johanek, T Hartke, B Shim, D Chen, M Ringkamp, R Meyer, S Raja;Johns Hopkins University, Baltimore, MDTreating neuropathic pain with systemic opioids is associated with sig-nificant dose-limiting central nervous system (CNS) side effects, toler-ance, and potential for addiction and drug abuse. Recent observationsuggests a role for peripheral mu-opioid receptors (MORs) in neuro-pathic pain. To examine whether selective activation of peripheralMORs may attenuate neuropathic pain behavior in rats, a blinded, ve-hicle-controlled study was designed to test whether loperamide, a pe-ripherally restricted MOR agonist, would attenuate the mechanical al-lodynia induced by ligation and transection of the L5 spinal nerve (SNL)in adult male rat. Paw withdrawal thresholds (PWT) to von Frey fila-ments were measured using the up-down method before and after drugadministration at different time points after nerve injury. The L5 SNLresulted in a significant decrease in PWTs on the injured side in animalsexamined at day 4 through day 42 post-SNL. Loperamide (s.c.) dose-dependently attenuated the mechanical allodynia in animals after SNL.The anti-allodynic effect of loperamide (1.5 mg/kg, s.c) was blocked bypre-treatment with naloxone hydrocholoride (10 mg/kg, i.p.), and alsoattenuated by peripherally acting MOR antagonist naltrexone methyl-bromide (5mg/kg, i.p.). Loperamide (1.5 mg/kg, s.c) was effective inattenuating mechanical allodynia even at 6 weeks post-SNL. Our obser-vations indicate that a peripherally selective MOR agonist, loperamide,can attenuate mechanical allodynia induced by nerve injury. These find-ings suggest that peripheral MORs may be an attractive therapeutictarget in the treatment of neuropathic pain, and peripherally actingselective MOR agonists may be a novel therapeutic approach for allevi-ating neuropathic pain.

S40 Abstracts