editorials
9. Samaniego F, Young D, Grimes C, et al. Vascular endothelial
growth factor and Kaposi’s sarcoma cells in human skin grafts. Cell
Growth Differ 2002;13:387-95.
10. El-Agroudy AE, El-Baz MA, Ismail AM, Ali-El-Dien B, El-Dien
AB, Ghoneim MA. Clinical features and course of Kaposi’s sarcoma
in Egyptian kidney transplant recipients. Am J Transplant 2003;3:
1595-9.
11. Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT
pathway in human cancer. Nat Rev Cancer 2002;2:489-501.
12. Kauffman H, Cherikh W, McBride M, et al. TOR inhibition
Combination Therapy for Neuropathic Pain — Which Drugs,
Which Combination, Which Patients?
Srinivasa N. Raja, M.D., and Jennifer A. Haythornthwaite, Ph.D.
Neuropathic pain is a complex, costly condition
resulting from a primary lesion or dysfunction in
any part of the nervous system, from the peripher-
al receptor to the brain. Degenerative spine disease,
diabetes, herpes zoster, compression and entrap-
ment syndromes, AIDS, surgeries such as thora-
cotomies and mastectomies, amputation, spinal
cord injury, and stroke are common causes of neu-
ropathic pain. The aging of the population and
the rising prevalence of many of these conditions
forecast a probable increase in the number of pa-
tients who will have neuropathic pain. Persistent
neuropathic pain usually alters a patient’s quality
of life by interfering with sleep, work, recreation,
and emotional well-being.
Although the causes of neuropathic pain are di-
verse, patients typically present with varying com-
binations of positive and negative signs and symp-
toms. Positive symptoms can result from changes
in the peripheral nerves, such as ectopic activity due
to injured sensory neurons and increased excit-
ability of adjacent uninjured neurons (peripheral
sensitization). A loss of inhibitory mechanisms in
the central nervous system and an increase in the
sensitivity of neurons in the spinal cord and high-
er centers (central sensitization) may also result
in positive symptoms. Ongoing pain, nonpainful
or unpleasant paresthesias, pain evoked by light
brushing of the skin (allodynia), and exaggerated or
prolonged pain from pinprick (hyperalgesia or hy-
perpathia) are positive features. These symptoms
may spread beyond the innervation territory of the
affected nerve. Negative symptoms reflect axonal
or neuronal loss and include sensory deficits in re-
sponse to touch, temperature, or pinprick.
Recent advances in pain research indicate mul-
tiple mechanisms underlying the initiation and
n engl j med 352;13 www.nejm.org
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maintenance immunosuppression is associated with a reduced inci-
dence of post-transplant malignancies. Presented at the 20th Inter-
national Congress of Transplantation Society, Vienna, September 5-
10, 2004. abstract.
13. Giral M, Nguyen JM, Daguin P, et al. Mycophenolate mofetil
does not modify the incidence of cytomegalovirus (CMV) disease
after kidney transplantation but prevents CMV-induced chronic
graft dysfunction. J Am Soc Nephrol 2001;12:1758-63.
Copyright © 2005 Massachusetts Medical Society.
maintenance of neuropathic pain.1 Ideally, eluci-
dating the mechanisms for pain in a patient could
lead to targeted, mechanism-based therapy.2 How-
ever, the similarity of symptoms among patients
does not imply common mechanisms, even when
the cause of the pain is the same.3 For some pa-
tients, the pathophysiology of the mechanisms
may primarily affect the peripheral nervous system,
whereas for others the predominant mechanisms
may affect the central nervous system.
The available therapies shown to be effective in
managing neuropathic pain include anticonvulsant
drugs, tricyclic antidepressant drugs, opioids, top-
ical lidocaine, new antidepressant drugs such as
duloxetine and venlafaxine, and the analgesic agent
tramadol.4,5 The anticonvulsant drug gabapentin
is used frequently to control pain in postherpetic
neuralgia and diabetic neuropathy, on the basis of
evidence of efficacy from randomized trials.6,7 The
mechanism of action in gabapentin is unclear, but
its effects on the a2d calcium-channel subunit may
result in the decreased release of neurotransmit-
ters and the suppression of central sensitization.
Opioids are also recommended as first-line treat-
ment for neuropathic pain.5 Although their use was
initially controversial, the benefits of opioids for
neuropathic pain have been shown in studies of in-
fused opioids, in a series of trials of oral medication,
and even in comparison with alternative thera-
pies.8 In a crossover study comparing opioids and
tricyclic antidepressant drugs in patients with post-
herpetic neuralgia, we observed similar reductions
in pain intensity with the use of opioids and antide-
pressants, but patients reported greater satisfaction
with opioid therapy.9 Like the majority of opioid
trials, our study used long-acting formulations
and around-the-clock doses. The use of short-act-
march 31, 2005 1373
 The new england journal
ing opioids is generally recommended only during
an initial titration period or as an adjunct to the
use of long-acting formulations to relieve break-
through pain.
In the clinical management of neuropathic
pain, when pain relief with gabapentin is incom-
plete, expert panels recommend adding a second
analgesic agent, which may be an opioid. Until now,
recommendations for combination therapy were
based on theoretical mechanisms, rather than on
controlled trials. In this issue of the Journal, Gilron
et al.10 provide evidence of the efficacy of a combi-
nation of gabapentin and morphine in reducing
pain and pain-related disability in patients with ei-
ther diabetic neuropathy or postherpetic neural-
gia. This double-blind, randomized, crossover trial
compared monotherapy and combination thera-
py with active placebo (lorazepam). As in clinical
practice, the study drugs were titrated with the ob-
jective of balancing analgesia and adverse effects.
The combination treatment with morphine and
gabapentin resulted in a greater reduction in pain
than did gabapentin alone, morphine alone, or pla-
cebo. The combination therapy also had beneficial
effects on pain-related interference with daily ac-
tivities, mood, and health-related quality of life.
The combination therapy resulted in a greater fre-
quency of constipation than gabapentin alone did
and a greater frequency of dry mouth than mor-
phine alone did. The use of an active comparator
drug is a particular strength of the trial design, and
few patients (25 percent) correctly identified when
they were receiving the gabapentin–morphine
combination.
The titration procedure allowed the study nurse
and the patients to find the best balance between
analgesia and adverse effects. It probably contrib-
uted to the relatively low rate of adverse effects
and enhances the generalizability of these findings
to clinical care. With concurrent titration, patients
stopped increasing the levels of gabapentin and
morphine at lower doses of each agent when the
two drugs were given in combination than they did
when receiving each as monotherapy. As a result,
treatment with the combination of gabapentin and
morphine yielded greater reductions in pain and
improvements in daily functioning with lower dos-
es of each medication than each did alone.
Practical issues arise in applying these find-
ings in clinical practice. For example, is combina-
tion therapy best given sequentially, as is typically
1374 n engl j med 352;13 www.nejm.org
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of medicine
recommended, or concurrently, as in the trial by
Gilron et al.? Sequential therapy offers the oppor-
tunity to identify patients who do not respond to a
single agent before the addition of a second agent.
This may be especially valuable in treating pa-
tients with coexisting conditions that require
multiple other medications or when drug interac-
tions should be taken into account. However, the
benefits of concurrent combination therapy shown
in this study, including lower doses with greater
pain relief and tolerable adverse effects, might be
due to the simultaneous titration of the two drugs.
The difference between recommended practice and
the method of Gilron et al. deserves critical scruti-
ny in the future to determine whether sequential
titration and concurrent titration of combination
therapies yield different outcomes.
Since clinical trials often select patients who
adhere maximally to study procedures and offer
them considerable support during drug titration,
actual adherence to combination therapy may be
substantially lower in routine clinical settings. Un-
fortunately, little is known about adherence in the
use of pain medications generally, but improved
adherence to therapy with opioids does occur with
a regular schedule of doses rather than with doses
given as needed.11 Although a combined formula-
tion was not used in this trial, such formulations
may improve adherence, as has been shown with
antiretroviral therapy.
Trials such as that conducted by Gilron and col-
leagues need to address additional challenges fac-
ing clinicians who are struggling to reduce neuro-
pathic pain in the individual patient. For example,
patients were satisfied with their pain relief and
stopped increasing drug doses at an average pain
level of 3 (on a scale from 0 to 10). How much pain,
if any, is acceptable to patients who have chronic
neuropathic pain? In deciding which treatment
and which combination to use, does the response
to a single agent predict the response to the combi-
nation? In deciding which treatment is appropriate
to which patient, can preexisting patient character-
istics, such as sex, genetic profile, and mechanisms
underlying the persistent pain, predict the response
to one agent as opposed to another? In deciding on
combination therapy, do additive or synergistic ef-
fects occur with some combinations and not with
others?
The study by Gilron et al. was not designed to
test whether combination therapy is synergistic, or
march 31, 2005
 editorials
even additive. Preclinical studies, however, suggest
a potential synergy between gabapentin and opi-
oids.12 It is important to ascertain whether the low-
er drug doses obtained with the use of the combi-
nation therapy extend to reduced tolerance or the
potential for abuse. Close examination of the data
in the present study10 suggests that prior exposure
to morphine may have reduced the beneficial ef-
fects of gabapentin. Identifying such subtleties in
treatment response will require large-scale investi-
gation.
As with various chronic conditions, the manage-
ment of neuropathic pain remains challenging in
many patients. This study clearly shows the advan-
tages of concurrent titration of gabapentin and mor-
phine, though the perceived risks of addiction and
diversion with opioids and the fear of scrutiny by
regulatory agencies may present barriers to the ac-
ceptance of this combination as first-line treatment.
In addition to developing and testing new pharma-
cologic agents, we need clinical trials that will ex-
amine which drugs in which combination, used for
which patients, provide effective pain relief with
the lowest doses and tolerable adverse effects.
Supported in part by grants (NIH-NS26363, to Dr. Raja, and NIH-
NS02225, to Dr. Haythornthwaite) from the National Institutes of
Health.
Dr. Raja reports having received compensation from an unre-
stricted educational grant awarded by Pfizer to the Johns Hopkins
University School of Medicine to develop a continuing medical edu-
cation teaching module. Dr. Haythornthwaite reports having received
a fee from Pfizer to review competitive grant applications for young
investigators.
n engl j med 352;13 www.nejm.org
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From the Departments of Anesthesiology and Critical Care Med-
icine (S.N.R.) and Psychiatry and Behavioral Science (J.A.H.),
Johns Hopkins University School of Medicine, Baltimore.
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march 31, 2005 1375