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 3521324-34

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 mechanismsno
  previous controlled trials had been done
• Until now

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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
• Creatinine
• 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

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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.

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Methods

• Treatment periods
• Lasted 5 weeks each
• First 3 wkdose titrated to max tolerable dose or
  TDD ceiling
• Week 4maintain max tolerated dose (primary
  outcome)
• Week 54 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.

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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.

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Demographic and Baseline Characteristics of the
Patients

• 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

Gilron, I. et al. N Engl J Med 20053521324-1334
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 (Pstatistically significant when compared to
  placebo.

22
Mean Daily Pain and Maximal Tolerated Doses of
the Study Drugs
Gilron, I. et al. N Engl J Med 20053521324-1334
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

24
Mean Daily Pain and Maximal Tolerated Doses of
the Study Drugs
Gilron, I. et al. N Engl J Med 20053521324-1334
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)
• Patients 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.

26
Mean (/-SE) Scores on the Short-Form McGill
Pain Questionnaire, Brief Pain Inventory, Medical
Outcomes Study 36-Item Short-Form General Health
Survey (SF-36 Health Survey), and Beck Depression
Inventory
Gilron, I. et al. N Engl J Med 20053521324-1334
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.

28
Adverse Effects
Gilron, I. et al. N Engl J Med 20053521324-1334
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.

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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

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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 werent 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 3521324-34.
• Raja SN, Haythornthwaite JA. Combination Therapy
  for Neuropathic Pain Which Drugs, Which
  Combination, Which Patients? N Engl J Med 2005
  3521373-75
• Bajwa ZH, Sami N, Ho CC. Antiepileptic drugs in
  the treatment of neuropathic pain. UpToDate (last
  update December 16, 2004)