Dextromethorphan Mitigates Phantom Pain in Cancer Amputees
Ron Ben Abraham, MD, Nissim Marouani, MD, and Avi A. Weinbroum, MD
Background: Hyperexcitability of N-methyl-
D
-aspartate (NMDA) receptors may play a role in
the persistence of phantom pain. Dextromethorphan (DM) blocks NMDA receptors.
Methods: Eight cancer and two noncancer amputees with established, disabling phantom pain
received oral DM 60 or 90 mg twice daily (BID) in a three-period double-blind crossover
placebo-controlled trial. This followed an open-phase trial in which either dose was given three
times daily if pain relief during the double-blind phase was Ͻ50% of pretreatment intensity. Patients
then underwent a 3-month phase of treatment with the best regimen and a subsequent 1-month
posttreatment follow-up.
Results: All patients reported a Ͼ50% decrease in pain intensity, better mood, and lower sedation
in each treatment phase. Four individuals reported this level of pain relief with the 60-mg and one
with the 90-mg BID regimen during the double-blind phase, whereas two amputees benefited from
the 60-mg and three from the 90-mg thrice-daily regimen in the open-phase trial. One reported
exacerbation of pain with the 90-mg BID regimen, and three reported pain rebound at the 1-month
posttreatment follow-up phase. Three patients stopped all previous analgesic use during the study.
Conclusions: Persistent phantom pain probably involves NMDA receptor hyperexcitability
because DM 120 to 270 mg/day mitigated the pain satisfactorily.
Key Words: Pain—Phantom—NMDA receptor—Antagonist—Dextromethorphan.
Phantom pain is considered an abnormal sensation
because it is perceived as coming from anatomical loca-
tions that no longer exist.
1
Although it was originally
described as occurring after the amputation of a limb, it
is also present after the amputation of other parts of the
body, such as the breast.
2
It is reported to occur in up to
two thirds of affected patients within the first 6 months
after the amputation.
3
In 5% to 10% of these patients, the
pain is described as being severe, persistent, and dis-
abling, as well as resistant to conventional therapy, such
as paracetamol, nonsteroidal anti-inflammatory drugs
(NSAIDs), propoxyphene, or even morphine.
2
Various
means for the attenuation of phantom pain have been
attempted, among them different anesthetic approaches,
surgical ablative therapies, or intrathecal stimulatory de-
livery systems, but they have often failed to provide
satisfactory pain relief.
4,5
The underlying pathophysiology of this unique
chronic pain syndrome remains obscure, with both pe-
ripheral and central neural mechanisms having been im-
plicated.
6
There is some evidence that excitability of the
dorsal horn neurons
7
is partly mediated by excitatory
amino acids acting at the N-methyl-
D
-aspartate (NMDA)
receptor sites, which, if antagonized, may block this
central excitability and its clinical manifestations.
8
This
is because spinal NMDA receptors cause amplification
and facilitation of pain transmission toward higher cen-
ters,
9
and their blockade was shown to have alleviated
the sensations of somatic and neuropathic pain in both
animal and human models.
9,10
Ketamine, a highly com-
petitive NMDA-receptor antagonist, was reported to re-
duce spontaneous pain in phantom pain,
11
but it has not
gained much clinical popularity because of its only par-
enteral route of administration and frequent dissociative
side effects. Recent studies with other NMDA receptor
antagonists also failed to demonstrate their having effec-
tiveness in chronic pain syndromes.
12,13
Received August 7, 2002; accepted October 28, 2002.
From the Post-Anesthesia Care Unit and Acute Pain Service, Tel
Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel
Aviv University, Tel Aviv, Israel.
Address correspondence and reprint requests to: Avi A. Weinbroum,
MD, Post-Anesthesia Care Unit, Tel-Aviv Sourasky Medical Center, 6
Weizman Street, Tel Aviv 64239, Israel; Fax: 972-3-692-5749; E-mail:
draviw@tasmc.health.gov.il.
Published by Lippincott Williams & Wilkins © 2003 The Society of Surgical
Oncology, Inc.
Annals of Surgical Oncology, 10(3):268–274
DOI: 10.1245/ASO.2003.08.007
268