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The role of dextromethorphan in pain control

Avi A. Weinbroum, MD^*,, Valery Rudick, MD^*, Gideon Paret, MD and Ron Ben-Abraham, MD^*

^* From the Department of Anesthesiology and Critical Care,
Post-Anesthesia Care Unit,
Tel-Aviv Sourasky Medical Center, and the Pediatric Intensive Care Unit, Sheba Medical Center, both affiliated with the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

Address correspondence to: Avi A. Weinbroum MD, Post-Anesthesia Care Unit, Tel-Aviv Sourasky Medical Center, 6 Weizman Street, Tel-Aviv 64239, Israel. Phone: +972-3-697-3237; Fax: +972-3-692-5749; E-mail: draviw{at}tasmc.health.gov.il

	Abstract

TOP Abstract Introduction SEARCH STRATEGY Excitatory amino acids and... Dextromethorphan - basic... The potential of... Evaluation of Dextromethorphan... Dextromethorphan in acute pain... Dextromethorphan in chronic and... Dextromethorphan and untoward... Conclusions References

 
Purpose: To review the clinical benefits of dextromethorphan (DM) in pain management, describe its neuropharmacological properties.

Source: A Medline search was made for experimental and clinical data on DM use from 1967 to date using keywords nociception, acute and chronic pain control, N-methyl-D-aspartate, antagonists, dextromethorphan.

Principle findings: The 930 DM citations mostly described its antitussive, metabolic and toxicological aspects, animal studies and its possible role in minimizing post-brain ischemia complications in humans. The use of DM in acute pain revealed eight original studies involving 443 patients, as well as two preliminary reports and our own unpublished data on 513 patients. Most of the 956 patients had general anesthesia. Eight studies (154 patients) and one case report dealt with chronic pain management. This N-methyl-D-aspartate (NMDA) receptor antagonist binds to receptor sites in the spinal cord and central nervous system, thereby blocking the generation of central acute and chronic pain sensations arising from peripheral nociceptive stimuli and enabling reduction in the amount of analgesics required for pain control. DM attenuated the sensation of acute pain at doses of 30-90 mg, without major side effects, and reduced the amount of analgesics in 73% of the postoperative DM-treated patients. Studies in secondary pain models in healthy volunteers and in various types of chronic pain showed DM to be associated with unsatisfactory pain relief.

Conclusion: DM attenuates acute pain sensation with tolerable side effects. Its availability in oral form bestow advantages over other NMDA antagonists.

	Introduction

TOP Abstract Introduction SEARCH STRATEGY Excitatory amino acids and... Dextromethorphan - basic... The potential of... Evaluation of Dextromethorphan... Dextromethorphan in acute pain... Dextromethorphan in chronic and... Dextromethorphan and untoward... Conclusions References

 
THE pharmacological management of acute postoperative pain and chronic pain syndromes has been traditionally based on various regimens of opioids and their congeners or NSAIDs. All opioids have side effects, of which the most dangerous are respiratory and cardiovascular depression associated with excessive sedation. NSAIDs may also induce side effects such as exacerbation of bleeding tendencies and impaired renal function. The search for alternative pain control strategies has focused on the N-methyl-D-aspartate (NMDA) receptors and their antagonists which were recently shown to alleviate somatic and neuropathic pain sensation in both animal and human models.^1–5 Their clinical utility stems from their ability to block the NMDA receptors located at the junction where pain generated by peripheral nociceptive stimuli is conveyed to central receptors via A and C sensory fibres.⁶ From a clinical standpoint, the amounts of conventional pain killers that are needed for effective pain control would be much smaller. One of these compounds is dextromethorphan (DM), a low-affinity, non-competitive NMDA receptor antagonist which has a long history of clinical safety as a cough suppressant.⁷

	SEARCH STRATEGY

TOP Abstract Introduction SEARCH STRATEGY Excitatory amino acids and... Dextromethorphan - basic... The potential of... Evaluation of Dextromethorphan... Dextromethorphan in acute pain... Dextromethorphan in chronic and... Dextromethorphan and untoward... Conclusions References

 
We conducted a Medline search of the English language literature using the following keywords: nociception, acute and chronic pain control, N-methyl-D-aspartate, antagonists, dextromethorphan. This review summarizes the neuropharmacological mechanism of action of DM, describes its clinical utility and limitations in different pain settings, i.e. acute, chronic, and neuropathic states, and also presents the published animal and clinical studies that had been carried out on the pain-control capabilities of this compound.

	Excitatory amino acids and modulation of NMDA receptors

TOP Abstract Introduction SEARCH STRATEGY Excitatory amino acids and... Dextromethorphan - basic... The potential of... Evaluation of Dextromethorphan... Dextromethorphan in acute pain... Dextromethorphan in chronic and... Dextromethorphan and untoward... Conclusions References

 
Considerable evidence has accumulated over the past few years on the role of excitatory amino acids (EAA), such as glutamate and aspartate, in modulating the sensation of pain via the ascending pathways along the spinal cord and central nervous system.⁶ The stimulation of NMDA receptors located in the dorsal horn of the spinal cord - the area responsible for relaying, modulating and transmitting pain - by intra-spinal deposition of glutamate in experimental rat and monkey models generated an increased response to noxious stimuli and lowered the threshold of pain.^8,9 This response was successfully abolished by NMDA antagonists, such as phencyclidine,⁹ suggesting that the initiation of pain can be attenuated by blocking the activity of these receptors. Investigations of chronic pain syndromes revealed that the same mechanisms are involved in the initiation and the perpetuation of secondary pain in mouse and rat models.^9,10

In terms of neurophysiology, following acute tissue injury, transduction is accomplished by action potentials being generated at the nerve endings and transmitted along the A and C fibres to the synapses of the dorsal part of the spinal cord where they induce the release of various peptides, including EAA.^8,9 The EAA activate the NMDA receptors that are located within the synapses, thus stimulating the synaptic neurones to transmit sensations of pain. This state of hyperexcitability, or "wind up" amplifies the magnitude and duration of neurogenic responses to any existing volley of nociceptive activity. Once initiated, this state of hyperexcitability can exist even after the peripheral input has ceased.¹¹ This phenomenon is currently thought to be responsible for various clinical pain syndromes such as allodynia, an intense sensation of pain following a relatively minor stimulus that would not ordinarily induce pain sensation or hyperpathia, a sensation of pain that persists long after the initial nociceptive stimulus has subsided.^9,10,12 The role of NMDA in the "wind up" phenomenon of pain perception was clarified in animals by intraspinal administration of NMDA-receptor antagonists.^13,14 In one human study, iv ketamine reduced the magnitude of both primary (immediate) and secondary hyperalgesia and the pain evoked by prolonged heat stimulation in a dose-dependent manner.¹⁵ DM acts in a similar manner: Klepstad et al. published a case report of a patient who had undergone four years of satisfactory ketamine treatment for postherpetic neuralgia: experimental substitution of the ketamine by DM 125 mg in four divided doses for seven days was found to be as efficient.²

It is important to note that the NMDA receptors are widespread throughout the central nervous system, and as such, are associated with highly diverse neurophysiological functions as far removed from the modulation of pain as learning and memory processing.¹ It is, therefore, not surprising that their antagonists can interfere with its physiological activity, leading to sedation, motor dysfunction or altered behavior.^1,9 Antagonism of the potentially deleterious effects of an excessive release of EEA, such as that which occurs in patients with focal brain ischemia (an example of diverse NMDA activity) can lead to episodes of agitation, hallucinations, somnolence, nausea, vomiting and nystagmus.^16–18 This is why so few NMDA-receptor antagonists have been tested in humans despite their effectiveness in pain management, and despite the extensive animal data that point to their promising beneficial effect.^19–21 To date, DM, ketamine and amantadine are the only drugs with NMDA-receptor antagonistic properties that are FDA-approved drugs for clinical use. However, due to the high affinity of ketamine to its receptors and its related dysphoric effects, together with the need to administer it intravenously, research in pain control has turned its focus to DM as the preferred NMDA antagonist for clinical use.

	Dextromethorphan – basic neuropharmacology

TOP Abstract Introduction SEARCH STRATEGY Excitatory amino acids and... Dextromethorphan - basic... The potential of... Evaluation of Dextromethorphan... Dextromethorphan in acute pain... Dextromethorphan in chronic and... Dextromethorphan and untoward... Conclusions References

 
Dextromethorphan and levorphanol were originally synthesized as pharmacological alternatives to morphine more than 40 yr ago. DM is the D-isomer of the codeine analogue, levorphanol but, in contrast to its L-isomer, it has no effect on the opioid receptors.²² From the beginning, its clinical use was mainly that of an antitussive in syrup preparations, at adult doses of 10 to 30 mg three to six times daily.⁷ The specific central sites upon which DM exerts its antitussive effect are still uncertain, but they are distinct from those of opioids, insofar as the effect is not suppressed by naloxone.²³ Also, unlike opioids, DM has an established safety record, i.e., the therapeutic cough suppressant dose (1 mg•kg^-1•dy^-1) has no major opioid-like respiratory or hemodynamic side effects, neither does it induce histamine released-complications.⁷

The binding of the antagonists to the NMDA receptors results in modifying the receptor-gated Ca²⁺ current. Changes in the Ca²⁺ current normally lead to NMDA-induced neuronal firing which, if it persists, is followed by a heightening of the intensity of the primary nociceptive stimulus, i.e., "wind up" phenomenon, and the triggering of secondary sensory pain.^24,25 In contrast to the other NMDA-receptor antagonists, DM has widespread binding sites in the central nervous system that are distinct from those of opioids and other neurotransmitters, so that its activity is not limited to the NMDA receptors alone, as was shown in pigs and rats.^26,27 Besides the ability of DM to reduce intracellular Ca²⁺ influx through the NMDA receptor-gated channels, DM also regulates voltage-gated Ca²⁺ channels which are normally activated by high concentrations of extracellular K⁺.²⁷ One of the physiological consequences of these multi-channel regulation capabilities is the attenuation by DM of NMDA-mediated neuronal firing in the brain that is normally transformed into seizures, as was shown experimentally in rats and in neurone cell cultures^25,28,29 as well as in humans (see below). The neuropharmacological cascade of events that provokes the reduced intracellular accumulation of Ca²⁺ to cause changes in the activity of NMDA receptors remains to be elucidated.

In humans as in animals, DM was also capable of ameliorating discomfort associated with excitotoxicity-related neurological disorders, such as intractable seizures and Parkinson's disease when administered at doses of 30 or 60 qid,³⁰ 45-180 mg od³¹ or 120 mg od³² for periods of three weeks to three months. No serious untoward neurological effects were detected in these and in another study where eight healthy human volunteers in whom motor cortex excitability (as indicated by motor-evoked potentials) was reduced after a single oral high (150 mg) dose.³³ In addition, motor cortex excitability and levodopa-induced dyskinesis were reduced by DM at a dose of 100 mg in a double-blind placebo-control study in patients with Parkinson's disease,³⁴ with only negligible side effects in this study as well.

Dextromethorphan is rapidly metabolized in the liver³⁵ where it is transformed to dextrorphan, its active and more potent derivative as an NMDA antagonist.²⁵ It was suggested that the side effects documented in clinical studies and attributed to the oral administration of DM might be mediated by this metabolite acting at the phencyclidine receptorial site rather than DM itself.³⁶

	The potential of Dextromethorphan in pain control

TOP Abstract Introduction SEARCH STRATEGY Excitatory amino acids and... Dextromethorphan - basic... The potential of... Evaluation of Dextromethorphan... Dextromethorphan in acute pain... Dextromethorphan in chronic and... Dextromethorphan and untoward... Conclusions References

 
Satisfactory pain control achieved with the least amount of opioids has always been an important goal in view of both the psychological and somatic dependence these drugs may induce and the often intolerable side effects that may follow their extensive use. The searchers for techniques of pain control that will afford full orientation, co-ordination and collaboration, and normal respiration as well as stable hemodynamics view these factors as important cornerstones in postoperative planning of pain control. This applies equally to patients who had undergone either general or regional anesthesia and to inpatients as well as outpatients. Moreover, in view of the contention that persistent NMDA receptor activation can evoke central hyperexcitability that can lead to secondary pain, proper pain control should both modulate primary pain sensation and preempt an analgesic state that would prevent acute pain from progressing into chronic pain. This concept of preemptive analgesia (i.e., reducing pain sensation in advance) is feasible via NMDA modulation, as had been demonstrated by the administration of opiates and ketamine to patients before surgery.^37,38 Importantly, this neuropharmacological receptor conditioning is also beneficial for reducing the need for additional doses of opioids postoperatively. In addition, while the neurovegetative stimulation and adrenergic overproduction that accompany the continuous neurally transmitted acute and, to a greater extent, secondary pain are clearly detrimental to all patients, they may be particularly harmful for cardiac patients. In this regard, the preemptive approach is an especially promising and beneficial one. The use of DM may, therefore, become an established component in protocols of treating pain and of alleviating the accompanying neurovegetative phenomena. Finally, the availability of DM in the oral form (indeed, in most human studies the administration was per os, Tables I and II) makes it much more preferable to the other anti-NMDA drugs that need to be injected, such as ketamine.

	Evaluation of Dextromethorphan efficacy

TOP Abstract Introduction SEARCH STRATEGY Excitatory amino acids and... Dextromethorphan - basic... The potential of... Evaluation of Dextromethorphan... Dextromethorphan in acute pain... Dextromethorphan in chronic and... Dextromethorphan and untoward... Conclusions References

 
While the methodology for evaluating postoperative pro-analgesic effects of DM in controlling acute pain in humans shares many features with commonly employed methods of assessment, for example double-blind study with randomization, other scales were also used among the various studies we retrieved (Table I):

I Objective scores

1. The total amount of postoperative analgesics consumed
   1. Opioids (morphine IV-PCA,^{39,42,44,45,50} Weinbroum et al., unpublished, meperidine im,^46,47 oral codeine⁴⁴)
      
   2. Non-steroidal anti-inflammatory drugs (diclofenac^5,39)
      
   3. Specific drugs (codydramol [paracetamol 500 mg + dihydrocodeine 10 mg]³⁹)
      
   
   
2. The time to first request of analgesic^5,46,47
   
3. Bed rest time^46,47
   
4. Sedation (0-10 VAS),^39,42 Weinbroum et al., unpublished.
   

II Patient self-evaluation

1. Pain intensity
   1. A verbal rating scale (0=none to 3=severe)⁴⁵
      
   2. Graded or analogue visual score (VAS, from 0 - no pain, to 10 or 100 – worst pain), ^{5,39,42,46-50} Weinbroum et al., unpublished
      
   3. Von Frey hairs⁵⁰ Weinbroum et al., unpublished
      
   
   
2. Pain relief
   1. Visual Analogue Scale (0-100)^42,48
      
   2. The time to onset of meaningful relief⁴⁸
      
   
   
3. Sedation
   1. Visual Analogue Scale (0-100) Weinbroum et al., unpublished
      
   
   

III Specific modes of assessment

1. One pediatric study⁴⁴ compared
   1. Admission vs discharge Children's Hospital of Eastern Ontario Pain Scale (CHEOPS)
      
   2. Children behavioral scale (1=asleep to 4= thrashing)
      
   3. Parental satisfaction rate (1-10 VAS).
      
   
   
2. Intraoperative DM usefulness was determined in one study based on blood pressure and heart rate⁴⁵
   
3. Written questionnaire one month postoperatively.⁵⁰
   

The evaluation of DM efficacy in patients with chronic pain is much more complicated because of ethical problems that do not allow the exclusion of a previously used analgesic, the many untoward side effects, and/or because of a possible ‘placebo effect’. Most of the studies on chronic pain were also double blind, and cross-over methods were used to minimize intersubject variability in response to (primary or secondary) pain or the learning phenomenon in volunteers^40,51 (Table II).

I Patient self-evaluation

1. Pain intensity (e.g.,)
   1. Verbal rating score⁵²
      
   2. 0-100 VAS^{2,4,40,41,52-54}
      
   3. Descriptive scale of eight words⁵² or 13 words⁵⁵
      
   4. Personal descriptive sensation (volunteers)⁴⁰
      
   5. The McGill Pain Questionnaire (20 groups of 78 descriptors)⁵²
      
   
   
2. Pain relief rating
   1. Categorical (none=0 to complete=4⁵² or = 5⁵⁵)
      
   2. Specific pain alleviation (e.g., allodynia⁵⁴)
      
   3. Daily treatment (0=poor, 4=excellent)⁵²
      
   
   
3. Personal feelings
   1. Mood (VAS, 0=worst to 100=best)⁵²
      
   2. Sleep quality (0=poor to 4=excellent)⁵²
      
   
   
4. Volunteer evaluation
   1. Pre- and post-drug alertness⁵¹
      
   2. Pain sensation (VAS)^4,51
      • Threshold to mechanical pressure (Von Frey hairs), puncture, electrical stimuli, heat
        
      • Post-insult contralateral hand pain
        
      
      
   
   
5. Cancer patients
   1. Magnitude of escalation in morphine requirement⁵³
      
   
   

II Objective findings

1. Pain intensity (VAS, categorical)⁵²
   
2. Pain relief (VAS, categorical)⁵²
   
3. Rate of compliance with treatment⁵⁵
   Nature of side effects^41,51-53,55
   1. Gastrointestinal, behavioral, or new pain onset
      
   2. Grade of tolerability or provoking withdrawal from study
      
   
   

	Dextromethorphan in acute pain control (Table I)

TOP Abstract Introduction SEARCH STRATEGY Excitatory amino acids and... Dextromethorphan - basic... The potential of... Evaluation of Dextromethorphan... Dextromethorphan in acute pain... Dextromethorphan in chronic and... Dextromethorphan and untoward... Conclusions References

 
The majority of the studies on the role of DM in attenuating acute postoperative pain or in reducing the consumption of analgesics compared one or two doses of oral DM premedication with placebo in patients who underwent surgery with general anesthesia (Table I). The pioneering study of Kawamata et al. showed that a single DM premedication of 30 or 45 mg (a dose used as a cough suppressant) administered 60 min before tonsillectomy under general anesthesia was effective in reducing post-tonsillectomy pain sensation, even upon swallowing, in adult patients.⁵ This single dose of DM also reduced the pain score and diclofenac requirement for the seven days following surgery. Henderson et al.³⁹ recently confirmed the efficacy of oral DM during the first two postoperative days in patients premedicated with 40 mg the night before and three times•dy^-1 for 48 hr after hysterectomy and with very few side effects (Table I). Two interesting studies also compared the efficacy of parenteral DM when given pre- as opposed to post-incisional.^42,46 According to the tested parameters, preincisional intravenous 5 mg DM was more efficacious than the same post-insult regimen, but the latter was accompanied by a high rate of side effects⁴² (Table I). The high incidence can be explained by the expected high plasma concentrations following the iv or im drug administration compared to a much lower one because of the low bioavailability (~10%) of DM after oral administration.^35,47 Support for this explanation can be found in two preliminary reports (Table I) which showed that 60 mg of oral DM preoperatively reduced postoperative pain, while 120 mg was not more efficient but rather evoked side effects.^48,49 Wu et al.⁴⁶ also compared the effect of pre- vs postincisional 40 mg DM given intramuscularly (im). They found that the former produced a better postoperative pain relief and reduced meperidine im consumption during the 48 hr following laparoscopic cholecystectomy in adult patients, compared to the postincisional patients. However, both regimens reduced the values of the tested parameters compared to otherwise matched patients who received a placebo. These authors recently reported having given preoperatively the same dose regimen to patients who underwent radical mastectomy under general anesthesia and that it resulted in an identical postsurgical decrease of pain and meperidine requirement.⁴⁷

These encouraging reports on the effects of oral DM on pain sensation are, however, challenged by the results of several double-blind studies on acute pain in which 255 patients did not benefit from DM (Table I). In one, DM at doses of 0.5 or 1.0 mg•kg^–1 did not reduce the pain score, analgesic requirement or other subjective and objective scores in children after tonsillectomy under multi-drug general anesthesia during the 24 postoperative hr⁴⁴ (Table I). These results that are in opposition to those found by Kawamata et al.,⁵ could be explained by the different study and drug protocols and in the age of the patients that could have accounted for their compliance with pain. Premedication with drugs that effect central function (Table I) could also have obscured DM effects and affected the interpretation of the results. In a recent study by McConaghy et al., oral 27 mg DM was given twice preoperatively and three times during the 24-hr after total abdominal hysterectomy.⁵⁰ Data from this study showed no benefit as expressed by VAS, MO consumption, etc., over placebo at 24 or 48 hr after surgery or one month later. Grace et al.⁴⁵ had earlier demonstrated that 60 mg DM given the night before surgery to non-premedicated patients scheduled for laparotomy under general anesthesia reduced the intraoperative morphine requirement based on blood pressure and heart rate, but not the postoperative patient-controlled morphine requirement. In view of the earlier mentioned study of Kawamata et al.,⁵ Grace et al.⁴⁵ suggested that, in order to reduce postoperative pain sensation and analgesic requirements, DM must be administered together with morphine, i.e., needs to be continued postoperatively. Wong et al.⁴⁷ suggested that the DM doses used by these latter studies were too low to produce analgesia because of the earlier described low oral bioavailability.

In a recent double-blind randomized study (Weinbroum et al., unpublished data), the postoperative morphine-sparing effect (compared to placebo) was confirmed for DM 60 or 90 mg only premedicated patients undergoing medium-sized low abdominal surgery under lidocaine epidural anesthesia. We suggest that nitrous oxide, which had been shown to block central sensitisation,^56,57 could have reduced afferent pain input, leading to only a marginal additional effect of DM over placebos. Indeed, Wu et al.,⁴⁶ whose patients underwent general anesthesia for laparoscopic cholecystectomy, still found that providing DM afforded the possibility of reducing the amount of meperidine after having anesthetized their patients with desflurane plus fentanyl and oxygen without nitrous oxide. It should be borne in mind that halothane, which, like desflurane, is a halogenated agent, was shown to antagonize N₂O-induced preemptive analgesia..⁵⁶ Moreover, in the study of Wu et al.,⁴⁶ patients were also preoperatively given benzodiazepines and atropine, two drugs with clear central modulatory effects on perception and attitude. Thus, a better understanding of the delicate mechanisms of interaction between DM, the NMDA receptor and possibly other factors that converge positively or negatively on NMDA receptor modulation of acute pain still awaits further confirmation from laboratory and clinical investigations.

	Dextromethorphan in chronic and neuropathic pain (Table II)

TOP Abstract Introduction SEARCH STRATEGY Excitatory amino acids and... Dextromethorphan - basic... The potential of... Evaluation of Dextromethorphan... Dextromethorphan in acute pain... Dextromethorphan in chronic and... Dextromethorphan and untoward... Conclusions References

 
The current understanding of the neuropharmacological role of NMDA antagonists in modulating chronic pain is still far from complete. A number of drugs with different neuropharmacological activities, such as sodium channel blockers,^58,59 opioids,^60,61 antidepressants,^62,63 or capsaicin,⁶⁴ were used with only moderate success and caused considerable side effects. Two excellent and comprehensive articles reviewed the complicated entity of neuropathic chronic pain, its pathophysiology and various therapeutic approaches that had been tested over the past few years.^65,66 Indeed, drugs that appeared promising for blocking the NMDA receptors in animal models of chronic pain^43,67 and in clinical trials (e.g., ketamine, amantadine)^68,69 not only did not provide satisfactory results in humans but even induced untoward neurological manifestations, including dysphoria, dissociative episodes and local irritation at the infusion site.^20,21 Elliot et al.⁷⁰ showed the ability of DM to suppress formalin-induced nociceptive behavior in a dose-dependent manner as well as a formalin-induced increase in spinal cord c-fos mRNA transcription (which is associated with NMDA receptor channel activation) in a rat model. In another model of chronic pain caused by sciatic nerve ligation in the rat, the intrathecal administration of DM reduced heat-evoked hyperalgesia.⁷¹ When compared to other NMDA receptor antagonists, such as MK-801and CGS 19755, the use of DM in the rat model of chronic pain after ischemic spinal injury proved to induce fewer side effects compared to the motor impairment and sedation caused by the other tested compounds.⁷² The particular potential of DM in reducing the "wind up" phenomenon which transforms acute pain into chronic pain syndromes and its oral availability made DM an ostensibly attractive drug in chronic pain management.^2,55 In addition, DM has a higher therapeutic ratio than, for example, ketamine, endowing it with a high safety profile even in prolonged administrations.⁷

Two thirds (72/110) of the patients involved in experiments simulating chronic pain or individuals who were actually suffering from various chronic pain syndromes had no benefit from DM at various doses detailed in Table II. No experimental studies showed satisfactory effects of DM used alone on secondary pain in volunteers. A single dose of 30 or 45 of DM given to six volunteers partially attenuated the secondary temporal summation of pain induced by thermal stimuli,⁴² while 100 mg given to eight healthy volunteers did not attenuate pain intensity induced by tourniquet ischemia to the hand, thermal stimuli or by topical capsaicin (a substance used for experimental induction of pain)⁵¹ (Table II). When these latter eight volunteers were given 200 mg DM, they all suffered from substantial side effects with no beneficial analgesia, leading four of them to withdraw from the study. In another study of 10 volunteers who were given 90 mg before capsaicin was injected intradermally, DM caused severe side effects in five of them and, again, no beneficial effect in any of them.⁴ In a burn injury study, when a single DM dose of 60 or 90 mg was given to 24 volunteers, it had only a slight inhibitory effect on the development of pinprick-induced hyperalgesia (Table II) but there still were some side effects.⁴⁰

The result of the few double-blind humans studies of DM in chronic and in neuropathic pain showed it to be ineffective for the most part. Contrary to the conclusions reached by Wong et al.,⁴⁷ this review of the literature supports the contention that the low dose regimen is not the cause for DM ineffectiveness. Perhaps it is because of the small number of patients enrolled in most studies or, alternatively, because of the many side effects that provoked patients to withdraw. This latter issue can be related to DM given in higher than clinically applicable doses, as had been established in animal protocols (Table II). McQuay et al.⁵² compared the analgesic effect of DM (40–80 mg•dy^-1) to placebo and found no difference in chronic neuropathic pain perception over two phases of 10-dy^-1 periods of surveillance. Mercadante et al.⁵³ in an open study - the only one done on patients with cancer-related pain - also found no benefit from a similar dose of DM 30 mg three times a day combined with either dextropropoxyphene or morphine and added to a previous multi-drug therapy. Dextromethorphan at higher doses 45-125 mg•dy^-1) for 7-14 dy^-1 in post-herpetic patients^2,54 (Table II) did alleviate pain in some of the patients, but evoked side effects. A much higher dose of DM, e.g., an incremental mean dose starting at 152 mg•dy^-1 in the first week of treatment and reaching a dose of 381 mg•dy^-1 at the sixth week given together with previous analgesic treatment to 14 patients with diabetic neuropathy (Table II), decreased the level of pain in only 24% of the patients.⁵⁵ A similar incremental dose trial, however, had no beneficial effect in a second group of 18 patients with postherpetic neuralgia. One patient from the first group and five from the second group were compelled to withdraw from the study because of intolerable side effects, while almost all of the other patients suffered from disturbing untoward effects (Table II). The discordant results in these two types of pathologies led the authors to suggest that NMDA antagonists could prevent neural arousal following ongoing noxious input due to ongoing damage, such as that which occurs in diabetic neuropathy, but not in the presence of "fixed" painful lesions, such as in postherpetic neuralgia. This and other explanations underline the complexity, heterogeneity and diversity of neural response in individual chronic pain syndromes.

	Dextromethorphan and untoward effects in pain control (Tables I, II)

TOP Abstract Introduction SEARCH STRATEGY Excitatory amino acids and... Dextromethorphan - basic... The potential of... Evaluation of Dextromethorphan... Dextromethorphan in acute pain... Dextromethorphan in chronic and... Dextromethorphan and untoward... Conclusions References

 
Dextromethorphan is considered to induce fewer side effects than other NMDA antagonists, partly because of its low affinity at its receptor site.⁷ The clear picture of the incidence of side effects and their gravity is somewhat limited because six studies of the 21 retrieved and herein discussed did not recount their presence or did report the incidence.^{39,40,44,45,48,49,} Also, several authors attributed the occurrence of untoward side effects to DM, although identical events at similar rates were recorded for the patients who received a placebo.⁵⁰ A survey of the well-documented adverse side effects of DM in its clinical dosing (45-90 mg•dy^-1 orally, Tables I and II) revealed that there were either no untoward effects^5,46 Weinbroum et al., unpublished data, or two main types of side effects, i.e., gastrointestinal and neurological, which were, however, tolerable and characteristically infrequent at low doses.^7,41 Higher doses (Table I) were associated with a higher incidence of side effects.^39,49,50,54 For example, patients who were given 120 mg orally instead of 60 mg DM preoperatively suffered from side effects that were absent when the lower dose had been given.⁴⁹ Studies that had used DM parenterally (Table I) or DM doses >100 mg in a single dose reported a rate of side effects as high 50% of the participants, and they included even behavioral effects as well.^{4,40,42,49,51,53,} The lack of side effects in the study of Wu et al.⁴⁶ might be explained by the chlorpheniramine that they had administered to the patients preoperatively. However, the rate of side effects was minimal if a high dose was divided into smaller portions.² Of 181 neurosurgical patients at risk for cerebral injury that were given protective courses of medium-to high doses of DM (0.8 to 9.64 mg•kg^-1•dy^-1), 89 reported tolerable and reversible side effects, without severe adverse reaction.⁷³ In this unique and analytic study, the authors demonstrated that the incidence of side effects was related to dose (higher in patients who were given DM >5 mg•kg^–1), serum concentration (>400 ng•ml^-1)l or brain concentration (>6000 ng•g^-1). The rate of side effects was also higher when dextrorphan, the active derivative, was found at high serum and brain concentrations. Interestingly, 55% of the patients that reported untoward effects were females compared with 45% males. Subjects in the age range of 26-40 yr had the highest rate. Importantly, a prolonged treatment and, consequently, a possible accumulative dose effect does not necessarily evoke severe side effects, as was shown after a period of two weeks where oral DM 45 or 90 mg was administered in postherpetic neuropathic patients⁵⁴ and as had been observed in patients with intractable seizures and Parkinson's disease after three weeks to three months of DM 30-180 mg•dy^-1.^30–32

The rate of side effects also appears to be higher when a DM dose of only 60 mg is co-administered with drugs that can themselves cause side effects or in patients who already suffer from chronic pain. They can occur with considerable ferocity in a very high percentage of these patients (up to 100%) and cause patients to withdraw from participating in the studies.^52,53 In addition to nausea and vomiting, dizziness, hot flushing, drowsiness, heartburn, headache and other untoward but reversible side effects in patients with neuropathic pain, there were rare complaints of respiratory depression,⁴⁶ intolerable pain or the onset of new pain,^51–53,55 to the extent that patients withdrew from chronic pain studies. This latter rare exacerbation of pain that occurred in chronic pain syndromes in which DM was added to a pre-existing analgesic treatment, was suggested to be the result of DM sensitizing the central neurons or exacerbating the spinal interneurons' state of excitation instead of inhibiting pain response as was shown in rats.^74,75 However, for obvious ethical reasons, DM cannot be used by itself while withholding daily treatment in chronic patients, especially in a double blind, placebo-controlled fashion.

	Conclusions

TOP Abstract Introduction SEARCH STRATEGY Excitatory amino acids and... Dextromethorphan - basic... The potential of... Evaluation of Dextromethorphan... Dextromethorphan in acute pain... Dextromethorphan in chronic and... Dextromethorphan and untoward... Conclusions References

 
Animal and clinical research indicate a beneficial role of NMDA receptor antagonists as part of multi-modal analgesic therapy, mainly for acute pain. For these patients, oral DM at doses of 30–90 mg appears to have an advantage over other antagonists in reducing the sensation of pain and sparing the requirement of conjointly administered analgesics, and has proven to have no or a low rate of untoward side effects. Further clinical trials, some currently now underway by the present authors, are still necessary to determine (1) the role of DM in various clinical pain-associated conditions, (2) the optimal clinical dose regimen that will considerably lower the rate of side effects, and (3) how long efficacious and safe treatment can be carried out both in acute and chronic pain syndromes.

	Acknowledgments

 
The authors wish to thank Esther Eshkol for her editorial assistance.

	Footnotes

 
This review was facilitated by aid from the "Anonymous Italian Family Foundation", Milan, Italy.

Accepted for publication March 3, 2000.

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TOP Abstract Introduction SEARCH STRATEGY Excitatory amino acids and... Dextromethorphan - basic... The potential of... Evaluation of Dextromethorphan... Dextromethorphan in acute pain... Dextromethorphan in chronic and... Dextromethorphan and untoward... Conclusions References

 
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