Dextromethorphan Mitigates Phantom Pain in Cancer Amputees
Ron Ben Abraham, MD, Nissim Marouani, MD, and Avi A. Weinbroum, MD
Background: Hyperexcitability of N-methyl-
-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
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.
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.
It is reported to occur in up to
two thirds of affected patients within the first 6 months
after the amputation.
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.
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.
The underlying pathophysiology of this unique
chronic pain syndrome remains obscure, with both pe-
ripheral and central neural mechanisms having been im-
There is some evidence that excitability of the
dorsal horn neurons
is partly mediated by excitatory
amino acids acting at the N-methyl-
receptor sites, which, if antagonized, may block this
central excitability and its clinical manifestations.
is because spinal NMDA receptors cause amplification
and facilitation of pain transmission toward higher cen-
and their blockade was shown to have alleviated
the sensations of somatic and neuropathic pain in both
animal and human models.
Ketamine, a highly com-
petitive NMDA-receptor antagonist, was reported to re-
duce spontaneous pain in phantom pain,
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.
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:
Published by Lippincott Williams & Wilkins © 2003 The Society of Surgical
Annals of Surgical Oncology, 10(3):268–274