The Evaluation of Morphine and Gabapentin in Combination for Neuropathic Pain

1. The Evaluation of Morphine and Gabapentin in Combination for Neuropathic Pain A Randomized Controlled Trial Justin Wu, M.D. April 13, 2005

2. The Article Morphine, Gabapentin, or Their Combination for Neuropathic Pain Gilron I, Bailey JM, Tu DS, Holden RR, Weaver DF, Houlden RL. N Engl J Med 2005; 352:1324-34

3. Background What agents do you use in your practice for the treatment of neuropathic pain?

4. Background Neuropathic pain is pain due to dysfunction of the nervous system in the absence of ongoing tissue damage. Common complication of diabetes, herpes zoster, compression and entrapment syndromes, degenerative spine disease, AIDS, amputation, spinal cord injury, and stroke.

5. Background Patients present with varying combinations of positive and negative signs and Sx. Positive Sx: ongoing pain, nonpainful or unpleasant parathesias, pain evoked by light touch, exaggerated or prolonged pain from pinprick. Negative Sx: sensory deficits in response to touch, temperature, or pinprick.

6. Background Available agents shown to be effective in pain management include anti-epileptic drugs, TCAs, opioids, new antidepressant drugs (duloxetine, venlafaxine) and tramadol (an analgesic). The use of gabapentin and opioids have been limited by incomplete efficacy, dose-limiting adverse effects, or both. A combination of mechanistically distinct agents may result in additivity or synergism, improving efficacy at lower doses with fewer side effects than using one drug alone.

7. Background Recommendations for combination therapy were previously based on theoretical mechanisms�no previous controlled trials had been done� Until now�

8. Goal To compare the efficacy of a combination of gabapentin and morphine with that of each as a single agent in patients with diabetic neuropathy or postherpetic neuralgia.

9. Methods Participants: recruited between 2/01-11/03 by advertisements and physician referrals. Diabetic neuropathy was determined by history and either an unequivocal decrease in response to pinprick, temperature, or vibration in both feet or bilaterally decreased or absent ankle-jerk reflexes. Patients with postherpetic neuralgia had an eruption of herpes zoster rash not more recently than 6 mo. before enrollment.

10. Methods Inclusion Criteria Daily moderate pain for 3 months or more Age 18-89 ALT or AST < 1.2x normal Creatinine < 1.5x normal Sufficient language skills to communicate to research staff.

11. Methods Exclusion Criteria Hypersensitivity to study meds Another painful condition as severe as the diabetic neuropathy or postherpetic neuralgia Recent MI, unstable angina or CHF Any central neurologic disorder Serious mood disorder Hx of serious drug or EtOH abuse Pregnancy, lactation Lack of a PCP

12. Methods Study design: Single-center, four-period, crossover, randomized trial 4 treatments compared: morphine, gabapentin, a combination of both, and an active placebo (low-dose lorazepam) Pts allocated in a double-blind, randomized fashion to one of four treatment sequences

13. Methods Study design (cont)�Blue (bid) and Gray (tid) capsules Morphine treatment Blue: SR Morphine 30mg Gray: lactose placebo Target Daily Dose (TDD): 120mg Gabapentin treatment Blue: lactose placebo Gray: Gabapentin 400mg TDD: 3200mg

14. Methods Combination treatment Blue: SR Morphine 15mg Gray: Gabapentin 300mg TDD: Morphine 60mg, Gabapentin 2400mg Placebo treatment Blue: Lorazepam 0.2mg Gray: Lorazepam 0.1mg TDD: 1.6mg

15. Methods Dose adjustments were made for age > 60 or wt < 60 kg Baseline diary: rated pain intensity 3x per day for 7days after d/c prev prescribed opioids or gabapentin Daily pain diary kept throughout study. Non-opioid drugs were permitted at a steady dose throughout the trial.

16. Methods Treatment periods: Lasted 5 weeks each First 3 wk�dose titrated to max tolerable dose or TDD ceiling Week 4�maintain max tolerated dose (primary outcome) Week 5�4 day dose tapering and 3 day complete washout Pt called twice weekly to evaluate adverse effects and guide drug titration

17. Methods Primary outcome: the mean intensity of pain (on a scale of 0-10, with 0 indicating no pain and 10 indicating �the worse pain imaginable�) Secondary outcomes Adverse effects Short-Form McGill Pain Questionnaire Brief Pain Inventory 36-Item Short-Form General Health Survey

18. Methods Analysis Multivariate (mixed linear) analysis was done to control for the treatment sequence and carryover effects.

19. Results Subjects: 57 patients underwent randomization 16 withdrew during the treatment periods (13 before completing the 2nd treatment period and 3 because of adverse effects) 41 patients completed the trial.

20. Patients with diabetic neuropathy (DN) = 35 Patients with postherpetic neuralgia (PN) = 22 Race: 56 white, 1 other Score for intensity of pain: DN = 5.8 +/- 1.8 PN = 5.6 +/- 1.6

21. Results Figure 2A: Weekly averages of daily pain scores for each treatment sequence. No significant main effects of either treatment sequence or treatment period were shown. The effects of drug treatment (P<0.001) were statistically significant when compared to placebo.

23. Results Primary Outcome = Mean Daily Pain (Fig 2B) during week 4 at the max tolerated dose of each regimen Baseline = 5.72 +/- 0.23 Placebo = 4.49 +/- 0.34 Gabapentin = 4.15 +/- 0.33 Morphine = 3.70 +/- 0.34 Combination = 3.06 +/- 0.33 Pain treated with the combination was rated lower than pain treated with morphine alone (P =0.04), gabapentin alone (P<0.001), or placebo (P<0.001)

25. Results Secondary Outcomes The mean maximum tolerated dose (in week 4) of morphine and gabapentin alone was higher than when used as part of the combination (Fig 2C) Patient�s scores (Table 2) for the Short-Form McGill Pain Questionnaire, the Brief Pain Inventory, SF-36 Health Survey and Beck Depression Inventory in general were significantly lower for the combination treatment than when compared to each agent alone.

27. Results Adverse Effects (Table 3) At the max tolerated dose, the combination treatment was associated with a lower frequency of constipation and anxiety than with each agent alone� However, the combination was also associated with a higher frequency of dry mouth, nausea, ataxia, edema, and blurry vision than either agent alone.

29. Results Blinding Questionnaire The percent of correct guesses by patients with regard to their treatment assignment were: Placebo = 66% Gabapentin = 42% Morphine = 44% Combination = 25%

30. Discussion Study Conclusions: Results of this study indicate that morphine, gabapentin, and the combination of both resulted in less pain in comparison to the placebo. Combination treatment results in less pain than treatment with either morphine or gabapentin alone. The combination treatment proved to be superior despite the use of lower mean doses of morphine and gabapentin than when each was used as a single agent. Some adverse effects were improved with the combination treatment, however others occurred in a higher frequency.

31. Discussion Study Conclusions (cont) Combination treatment had beneficial effects on pain-related interference with daily activities, mood, and health-related quality of life. This trial replicates previous studies of the efficacy of opioids in neuropathic pain. Given the potential benefits and drawbacks of any drug combination, additional trials are needed to compare other analgesic combinations.

32. Discussion Strengths: Randomized, double-blind, controlled trial Active placebo (lorazepam) used that mimics the adverse effects of the active treatments without producing analgesia Blinding questionnaire (only 25% of patients receiving combination therapy correctly identified their regimen) No patients were excluded from the analysis because of missing data

33. Discussion Limitations: Only 2 types of neuropathic pain studied No analysis provided comparing the effects of each treatment regimen on each type of pain Homogenous patient population

34. Discussion Relevance Although participants weren�t exactly similar to our patient population (ethnicity, chronic illness, substance abuse), results are probably generalizable. Actual adherence to combination therapy may be lower in clinical practice.

35. Discussion Further questions to pursue: Other combinations of therapy need to be studied. Is there additivity or synergism involved? (pharmacologic mechanisms) Do the lower doses obtained with the combination regimen extend to a reduced tolerance or a reduced potential for abuse? Is combination therapy best given sequentially or concurrently?

36. Discussion Will this study change your management of neuropathic pain?

37. References Gilron I, Bailey JM, Tu D, Holden RR, Weaver DF, Houlden RL. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med 2005; 352:1324-34. Raja SN, Haythornthwaite JA. Combination Therapy for Neuropathic Pain� Which Drugs, Which Combination, Which Patients? N Engl J Med 2005; 352:1373-75 Bajwa ZH, Sami N, Ho CC. Antiepileptic drugs in the treatment of neuropathic pain. UpToDate (last update December 16, 2004)