Title: The Evaluation of Morphine and Gabapentin in Combination for Neuropathic Pain
1The Evaluation of Morphine and Gabapentin in
Combination for Neuropathic Pain
- A Randomized Controlled Trial
- Justin Wu, M.D.
- April 13, 2005
2The 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
3Background
- What agents do you use in your practice for the
treatment of neuropathic pain?
4Background
- 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.
5Background
- 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.
6Background
- 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.
7Background
- Recommendations for combination therapy were
previously based on theoretical mechanismsno
previous controlled trials had been done - Until now
8Goal
- 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.
9Methods
- 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.
10Methods
- 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.
11Methods
- 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
12Methods
- 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
13Methods
- 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
14Methods
- 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
15Methods
- 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.
16Methods
- 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
17Methods
- 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
18Methods
- Analysis
- Multivariate (mixed linear) analysis was done to
control for the treatment sequence and carryover
effects.
19Results
- 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.
20Demographic 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
21Results
- 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.
22Mean Daily Pain and Maximal Tolerated Doses of
the Study Drugs
Gilron, I. et al. N Engl J Med 20053521324-1334
23Results
- 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
24Mean Daily Pain and Maximal Tolerated Doses of
the Study Drugs
Gilron, I. et al. N Engl J Med 20053521324-1334
25Results
- 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.
26Mean (/-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
27Results
- 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.
28Adverse Effects
Gilron, I. et al. N Engl J Med 20053521324-1334
29Results
- Blinding Questionnaire
- The percent of correct guesses by patients with
regard to their treatment assignment were - Placebo 66
- Gabapentin 42
- Morphine 44
- Combination 25
30Discussion
- 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.
31Discussion
- 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.
32Discussion
- 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
33Discussion
- 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
34Discussion
- 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.
35Discussion
- 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?
36Discussion
- Will this study change your management of
neuropathic pain?
37References
- 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)