Correspondence

Morphine, Gabapentin, or Their Combination for Neuropathic Pain

N Engl J Med 2005; 352:2650-2651June 23, 2005

Article

To the Editor:

The cleverly designed and carefully conducted crossover trial reported by Gilron et al. (March 31 issue)1 shows better control of neuropathic pain with the combination of morphine and gabapentin than with single agents or placebo. Although we admire the meticulousness of the investigators, we also marvel at the unusually rigid adherence of the majority of the patients to a demanding and complex drug regimen. We must conclude that this was a very select group of highly motivated and fastidious patients. It is likely that they had many more personality traits in common with one another than with the general population.

Given that an improvement in mood is associated with a reduction in the perception of pain severity, a finding again replicated in this study, it is likely that the response to any drug therapy is highly dependent on personality. This leads us to question whether this result can be applied to the rest of patients who have neuropathic pain. Further studies are needed to determine the effectiveness of this combination in clinical practice.

J. Kenneth Baillie, M.B., Ch.B.
Ian Power, M.D.
Royal Infirmary, Edinburgh EH16 4SU, United Kingdom
j.k.baillie@doctors.org.uk

1 References

1. 1

   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;352:1324-1334
   Full Text | Web of Science | Medline

To the Editor:

Gilron et al. report the superior efficacy of gabapentin and morphine combined in relieving neuropathic pain. Additional information might further elucidate their important findings.

First, was the neurologic assessment scored to fulfill minimal criteria for the diagnosis of diabetic peripheral neuropathy?1,2 In elderly patients, decreased or absent ankle reflexes alone are not diagnostic of neuropathy.3 Were peripheral pulses assessed, since peripheral vascular disease, which is common in diabetes, is associated with pain? Also, since glycemic control influences the intensity of pain, were additional measurements of glycosylated hemoglobin performed over the five months of the study?

Second, we were surprised that 40 percent of the patients with diabetes had not had any pain-relieving drugs prescribed previously. If these patients had milder pain, could this have influenced the results? Is first-line use of combination treatment in such cases necessary?

Solomon Tesfaye, M.D.
Dinesh Selvarajah, M.B., Ch.B.
Royal Hallamshire Hospital, Sheffield 210 2JF, United Kingdom

3 References

1. 1

   Scott LA, Tesfaye S. Measurement of somatic neuropathy for clinical practice and clinical trials. Curr Diab Rep 2001;1:208-215
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   Report and recommendations of the San Antonio conference on diabetic neuropathy. Diabetes Care 1992;15:Suppl 3:1080-1107
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   Dyck PJ, Litchy WJ, Lehman KA, Hokanson JL, Low PA, O'Brien PC. Variables influencing neuropathic end-points: the Rochester Diabetic Neuropathy Study of Healthy Subjects. Neurology 1995;45:1115-1121
   Web of Science | Medline

Author/Editor Response

The detailed neurologic assessments that were performed in patients who were being evaluated for this trial were not scored. These patients were screened by means of a detailed interview and review of all available medical records, a physical examination (including, but not limited to, neurologic and cardiovascular examinations — with routine assessment of peripheral pulses), and laboratory or special tests, or both, that were necessary to confirm the diagnosis of postherpetic neuralgia or of distal, symmetric, sensory diabetic polyneuropathy, and among patients with diabetic neuropathy, to rule out other nutritional, endocrine, toxic, and immune-mediated causes.1 There were no patients enrolled in the trial with decreased or absent ankle reflexes as the only abnormal neurologic finding. Measurements of glycosylated hemoglobin were not repeated after the trial had begun.

We, too, were unpleasantly surprised by the degree of undertreatment of pain among our patients. Data from a patient survey by our group support this observation, which we have recently discussed.2 The mean score for baseline pain intensity ranged from 5.6 to 5.8 on a scale from 0 to 10, indicating at least moderate pain (a score above 4) in almost all patients. Therefore, the apparently high degree of undertreatment was not a reflection of milder pain among our study patients.

In the setting of chronic pain, patients' compliance with treatment is generally higher than in that of other conditions (e.g., hypertension), where symptomatic improvement is not readily appreciated.3 Thus, greater compliance may also be expected in analgesic trials. Furthermore, the rate of withdrawal from our trial was similar to dropout rates in previous studies of similar complexity and duration.4 Nevertheless, the generalizability of trial results to broader populations and diverse treatment settings is never implicit, and research findings must be viewed from a clinical perspective when treatment is being individualized. With regard to combination analgesic therapy, the anticipated benefits of polypharmacy need to be weighed against possible problems, such as the increased risk of medication errors, decreased compliance, and the potential for adverse drug interactions.5 With these issues taken into consideration, this study provides evidence in support of the benefit of combining gabapentin and morphine for neuropathic pain.

Ian Gilron, M.D.
Queen's University, Kingston, ON K7L 2V7, Canada
gilroni@post.queensu.ca

Donald F. Weaver, M.D., Ph.D.
Dalhousie University, Halifax, NS B3H 4J3, Canada

5 References

1. 1

   Diabetic polyneuropathy in controlled clinical trials: consensus report of the Peripheral Nerve Society. Ann Neurol 1995;38:478-482
   CrossRef | Web of Science | Medline

2. 2

   Gilron I, Bailey J, Weaver DF, Houlden RL. Patients' attitudes and prior treatments in neuropathic pain: a pilot study. Pain Res Manag 2002;7:199-203
   Medline

3. 3

   Berndt S, Maier C, Schutz HW. Polymedication and medication compliance in patients with chronic non-malignant pain. Pain 1993;52:331-339
   CrossRef | Web of Science | Medline

4. 4

   Sang CN, Booher S, Gilron I, Parada S, Max MB. Dextromethorphan and memantine in painful diabetic neuropathy and postherpetic neuralgia: efficacy and dose-response trials. Anesthesiology 2002;96:1053-1061
   CrossRef | Web of Science | Medline

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   Virani A, Mailis A, Shapiro LE, Shear NH. Drug interactions in human neuropathic pain pharmacotherapy. Pain 1997;73:3-13
   CrossRef | Web of Science | Medline

Citing Articles (5)

Citing Articles

1. 1

   Elham Saghaei, Taraneh Moini Zanjani, Masoumeh Sabetkasaei, Kobra Naseri. (2012) Enhancement of Antinociception by Co-administrations of Nefopam, Morphine, and Nimesulide in a Rat Model of Neuropathic Pain. The Korean Journal of Pain 25:1, 7
   CrossRef

2. 2

   Tanja E. Hamm-Faber, Hans A. Aukes, Frank de Loos, Ismail Gültuna. (2011) Subcutaneous Stimulation as an Additional Therapy to Spinal Cord Stimulation for the Treatment of Lower Limb Pain and/or Back Pain: A Feasibility Study. Neuromodulation: Technology at the Neural Interfaceno-no
   CrossRef

3. 3

   G. J. Ebenezer, R. O'Donnell, P. Hauer, N. P. Cimino, J. C. McArthur, M. Polydefkis. (2011) Impaired neurovascular repair in subjects with diabetes following experimental intracutaneous axotomy. Brain 134:6, 1853-1863
   CrossRef

4. 4

   Sabine Sator-Katzenschlager, Katharina Fiala, Hans G. Kress, Alexandra Kofler, Josef Neuhold, Herwig Kloimstein, Wilfried Ilias, Eva-Maria Mozes-Balla, Michaela Pinter, Nadja Loining, Wolfgang Fuchs, Georg Heinze, Rudolf Likar. (2010) Subcutaneous Target Stimulation (STS) in Chronic Noncancer Pain: A Nationwide Retrospective Study. Pain Practice 10:4, 279-286
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5. 5

   Raquel Lana, Ana Isabel Lérida, Juan Luis Mendoza. (2008) Tratamiento del dolor neuropático en el enfermo con infección por el VIH. Enfermedades Infecciosas y Microbiología Clínica 26:6, 348-355
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