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Anesth Analg 2001;92:448-454
© 2001 International Anesthesia Research Society

REGIONAL ANESTHESIA AND PAIN MEDICINE

Large-Dose Oral Dextromethorphan as an Adjunct to Patient-Controlled Analgesia with Morphine after Knee Surgery

Anupama Wadhwa, MB, BS, DA, David Clarke, MBBS, Colin S. Goodchild, MA, MB, BChir, PhD, FRCA, FANZCA, FFPMANZCA, and David Young, MBBS, FRACS*

Monash University Department of Anaesthesia, Clayton, Victoria, Australia and *The Avenue Hospital, Melbourne Victoria

Address correspondence and reprint requests to Professor Colin S. Goodchild, Monash University Department of Anaesthesia, Level 5 Block E, Monash Medical Centre, 246 Clayton Road, Clayton Victoria 3168, Australia. Address e-mail to colin.goodchild @med.monash.edu.au.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Dextromethorphan is a weak N-methyl-d-aspartate (NMDA) receptor antagonist that inhibits spinal cord sensitization in animal models of pain and also inhibits the development of cutaneous secondary hyperalgesia after tissue trauma. Perhaps coadministration of an NMDA antagonist with an opioid would lead to better pain relief, particularly with movement and an opioid-sparing effect. This has been shown for ketamine, but previous studies with dextromethorphan that have used small doses have shown only a modest reduction in morphine requirements with no or minimal changes in the postoperative pain experience. We sought to determine whether a large dose of this drug, just below the maximum tolerated dose, could potentiate morphine analgesia while simultaneously causing a significant improvement in the management of the postoperative pain experience. Sixty-six patients undergoing knee surgery were enrolled in the study. The study design was a prospective, randomized double-blinded comparison with placebo of 200 mg of dextromethorphan given eight hourly. Postoperative pain experiences were assessed by postoperative morphine usage. Visual analog and verbal rating scales were used to assess pain with movement as well as side effects. Dextromethorphan treatment led to a significant but modest reduction in morphine requirements (29.3% P < 0.05) but no reduction in postoperative pain levels. We conclude that increasing orally administered dextromethorphan to near maximum tolerated doses does not provide greater morphine sparing than 20–40 mg given 6–8 hourly as in previous studies. Furthermore we conclude that dextromethorphan does not improve pain scores in a manner expected of a drug with NMDA antagonist properties.

Implications: Although dextromethorphan is an N-methyl-d-aspartate antagonist in animals, this property may not be realizable in human postoperative pain states.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Pain after injury is accompanied by pain experienced at rest and often exacerbated by touching of the wound or movement of the injured body part. The extra pain associated with touching or movement is because of a process known as spinal cord sensitization (1–4). Central to the development of spinal cord sensitization is the activation of N-methyl-d-aspartate (NMDA) receptors, which are located in the spinal cord dorsal horn (5,6). The discovery of NMDA antagonist properties of small doses of the anesthetic drug ketamine has led to its successful use in the management of postoperative pain states. It causes simultaneous reduction in opioid usage and improvements in movement pain scores (3,7). As far as an oral preparation is concerned, dextromethorphan might also fulfill a role similar to ketamine. Dextromethorphan is a morphinan that has been used as an antitussive drug for 40 years. More recently it has been shown to possess weak noncompetitive NMDA antagonist properties targeting the sigma site (8). In animals, this drug decreases spinal cord sensitization when given at a large dose. In human experimental pain models, dextromethorphan inhibited the development of cutaneous secondary hyperalgesia and reduced temporal summation of pain (9–12).

However, studies of postoperative pain using doses of dextromethorphan from 40 mg as a single preemptive dose up to 350 mg by infusion have shown inconsistent results, with some reporting morphine sparing of approximately 20–30% and others minimal or no improvements in the postoperative pain experience (13–16). If dextromethorphan were given in an effective dose as an NMDA antagonist, these studies would show an improvement in pain scores, particularly with respect to movement as well as reduction in morphine usage. No dose-response relationship for this effect in humans has been demonstrated. This led to the conception of this trial. We decided to test the maximum tolerated dose of this compound to ascertain whether improvement in movement pain scores could be achieved. Because dextromethorphan is a rather weak NMDA antagonist, we decided to perform a randomized double-blinded comparison with placebo of dextromethorphan given at the largest dose possible without unacceptable side effects. The study reported here is in two parts. The first part was a dose escalation study in postoperative patients to determine the maximum tolerated dose of dextromethorphan that could be given orally to humans after surgery. The second part of the study involved giving a slightly smaller dose than the maximum tolerated dose divided into three increments given at 8-h intervals. The patients in the two groups were matched for operation type. They also received the same standardized anesthetic and postoperative regime that involved passive movements of the operated knee joint using a continuous passive movement machine (CPM). Apart from the morphine taken from a patient-controlled analgesia device (PCA), the pain associated with passive movement of the operated knee was assessed with visual analog and verbal rating scales.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Institutional ethics committee approval was obtained before each part of this study, and written informed consent was obtained from all patients. In the first part of the study, 25 patients undergoing surgery involving the lower limbs (hip or knee surgery) aged 18–60 yr were recruited. In the second part of the study, 66 patients undergoing knee surgery (reconstruction or replacement) aged between 18 and 74 yr were included. In both parts, patients were prospectively randomized to placebo or dextromethorphan treatment. In the second part of the study stratification of the randomization process was performed to ensure roughly equal numbers in the placebo and active groups having knee replacements (aged 53–74 yr) and knee reconstruction surgery (aged 18–41 yr). All patients were male or nonpregnant, nonlactating female patients practicing adequate birth control, ASA I–III who were willing to have a general anesthetic and able to use a PCA machine. The patients were screened to ensure that they had not participated in any clinical trials in the month before surgery and they were willing to comply with the protocol. Patients were excluded if they had a history of chronic pain or opioid abuse or had clinically significant renal or hepatic impairment or a history of intractable vomiting after previous surgery. Patients were excluded from the trial if they had taken codeine, aspirin or nonsteroidal antiinflammatory drugs (other than diclofenac) within 6 h before surgery. If the patient was unable to communicate adequately in the English language, they were excluded, as were those taking drugs that interfere with the metabolism of dextromethorphan, such as monoamine oxidase inhibitors central nervous system depressants, SSRI inhibitors, amiodarone, and quinidine. Fluoxetine was allowed as long as the preoperative morning dose was not given. Before obtaining written consent for the trial, the whole procedure was explained to the patients preoperatively. After a full physical examination and medical history, they were familiarized with the use of the PCA machine and sensory assessments used postoperatively to evaluate pain experiences and side effects.

Active drug and placebo gelatin capsules were manufactured and supplied by the Institute of Drug Technology for FH Faulding & Co., Ltd. Australia. Identical size gelatin capsules were available in dextromethorphan dose strengths of 50 mg, 100 mg, 150 mg, 200 mg, 400 mg, and 500 mg. Matching placebo capsules containing lactose were also manufactured by the Institute of Drug Technology and supplied by Faulding. Each patient’s treatment was dispensed by the hospital pharmacy in an individual bottle identified only by the patient’s randomized treatment number.

In the first part of the trial, dextromethorphan doses were given on an escalating scale in 50-mg increments starting at 50 mg with one in five patients randomized to receive placebo. The protocol provided for the same or a reduced dose of dextromethorphan to be given to the next patient randomized to receive active treatment should there have been dose-limiting side effects. The principal investigator (CSG) was responsible for determining the dose based on the previous patient’s side effects. All patients received two identical capsules so that the observers and patient were unaware of the nature of the treatment. A standardized anesthetic technique was used for the surgery in all patients. The patients were premedicated with 10–20 mg of temazepam 2 h before surgery, and anesthesia was induced with an IV injection of propofol followed by a muscle relaxant given at the discretion of the anesthetist. No local anesthetic blocks were used. The assessor administered the study medication in the recovery room when the patient was sufficiently awake to tolerate oral medication and to use the PCA machine. Side effects were assessed at the time of oral dosing and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, and 12 h after that. In addition, routine postoperative monitoring was continued for 24 h, including pulse, blood pressure, and oxygen saturation. The maximum tolerated dose was defined as the largest dose achieved in the escalation that was not associated with severe side effects such as nausea with vomiting on more than one occasion, heavy sedation, or hallucinations.

The second part of the study was a prospective, randomized placebo-controlled trial. The study medication or placebo was administered 2 h before the expected time of surgery and then 8 and 16 h after that. The pharmacist dispensed the drug according to a computerized randomization protocol. As a maximum tolerated dose of 750 mg was identified in part one of the study, it was initially decided for this to be administered as 400 mg in the initial dose of dextromethorphan followed by two 200-mg increments at 8-h intervals. However, there was a very frequent incidence of side effects such as severe rash, nausea and vomiting in more than 50% of the patients after the 400-mg dose. Thus for the main trial, the initial dose and the subsequent 8 hourly doses of dextromethorphan were all 200 mg each. This protocol change was achieved centrally with the pharmacy and FH Faulding without altering the blinding of patients or observer. The patients were excluded from data analysis after study completion. The five placebo patients studied before the protocol change remained in the analysis. Thus all patients recruited to the study were followed to study completion with the patient and observer unaware of the nature of the treatment. The protocol did not change with respect to observations and visits. There was a policy throughout the study that subsequent doses of test medication would be withheld from any patient experiencing severe side effects that might have been a result of dextromethorphan treatment.

The patients were given a standardized anesthetic, which included the induction of anesthesia with IV injections of 2 mcg/kg fentanyl, propofol at the rate of 10 mg every 2 s until loss of eyelid reflex, and then a muscle relaxant at the discretion of the anesthetist. Anesthesia was maintained using nitrous oxide in oxygen plus isoflurane that was adjusted to maintain adequate depth of anesthesia. Analgesia was maintained during the operation by the administration of 1 mcg/kg fentanyl every half-hour. Muscle relaxation was reversed at the end of the case with atropine and neostigmine and antiemetics were administered according to the discretion of the anesthetist.

In the recovery room, for every patient the operated knee was placed in a CPM that moved the knee joint through an angle of flexion of 50 degrees at a speed of 1–5 times per minute. This was continued until 24 h after the first dose of dextromethorphan unless the patient had such severe pain not controlled with morphine from the PCA or there was bleeding in excess of 1500 mL into the drains. The patients were given an initial dose of morphine from the PCA machine if required in recovery and then they were allowed control of the machine. The PCA was set to deliver morphine dose increments of 1 mg with a lockout period of 5 min. Oxygenation was recorded from a pulse oximeter attached to the patient for the first 24 h after surgery. Postoperative pain experiences were assessed while the patient was on the CPM machine using a visual analog scale (VAS), a 10 cm line marked at one end "no pain" and at the other "very severe pain" and a four-point verbal rating scale of none, mild, moderate, or severe. The morphine requirements taken from the PCA machine along with the pain rating scales were measured postoperatively at the following time points with respect to the initial capsule administration: 4, 6, 8, 12, 16, 20, and 24 h. At these same times the patients were assessed for side effects using verbal rating scales for sedation, nausea and vomiting, respiratory depression, hallucinations, lightheadedness, slurred speech, gaze evoked nystagmus, lack of coordination, spasticity, and facial numbness.

A power analysis was performed before the study. Values for standard deviation for morphine usage from a PCA machine and VAS scores on movement in patients having similar surgery were obtained from published papers (17,18). These were 20 mm for the VAS and 50 ± 15 mg (mean ± SD) morphine usage from PCA at 24 h. These figures were used to calculate the number of subjects needed in each group for an 80% chance of detecting a 25% reduction in morphine usage at 24 h and a 30% reduction in VAS scores with {alpha} = 0.05 (19). This value was 22. One of these studies (17), also addressed the issue of gender difference. The authors observed that the 24-h morphine consumption from PCA for "peripheral" surgery was 57 mg for males and 56 mg for females. Therefore, if a gender imbalance occurred despite randomization, one would not expect that to alter the postoperative PCA morphine usage for this type of surgery

Student’s t-test was used to compare morphine usage from PCA at 24 h by both groups of patients and contingency tables for the verbal rating scales were analyzed with a {chi}2 test. In all cases, a P value <0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
In the first part of the trial, 25 patients were recruited although one was subsequently withdrawn because the surgery required a plaster cast. The dose escalation protocol continued unhindered until Patient 21, who experienced dose-limiting side effects, i.e., severe slurred speech and lightheadedness followed by deep sedation. This patient had received 800 mg of dextromethorphan, and thus Patient 22 received 750 mg. That patient, as well as the previous patient who received 750 mg (Patient 20), experienced no dose-limiting side effects. Patients 24 and 25 also received 800 mg and both of them experienced dose-limiting side effects in the form of lightheadedness followed by deep sedation. Patient 24 also experienced upsetting hallucinations. Thus the trial was terminated at this point with all three patients that had received 800-mg dextromethorphan experiencing severe dose-limiting side effects. It was concluded that the maximum tolerated dose was 750 mg in this group of postoperative patients who were receiving morphine from PCA for postoperative pain relief.

This led to the second phase study, in which it was planned to give patients 800 mg dextromethorphan in three divided doses, an initial dose of 400 mg preoperatively followed by two doses each of 200 mg 8 and 16 h after that. In this second phase of the trial, 66 patients were recruited. Thirty-three of these patients had knee replacement surgery and thirty-three had knee reconstruction. Of these, five were excluded, as they did not fit the criteria of the study after their inclusion. One of these patients had signed to participate in another trial. Two patients did not go ahead because the surgeon found at operation that a medial meniscus tear precluded anterior cruciate ligament reconstruction. One patient was removed because of a protocol violation. Another patient had a difficult knee replacement and the surgeon advised that postoperative physiotherapy using a CPM machine was contraindicated. The first five treated patients were excluded after they had received 400 mg dextrome-thorphan as their first dose because of adverse events such as severe rash or nausea and vomiting. These patients were not given subsequent doses because of these side effects. The observations and visits in those patients continued as with other patients because the observer was unaware of what medication the patient had received. After the trial was completed these patients were withdrawn from the trial analysis. This left 22 patients in the treatment group who received 200 mg of dextromethorphan for all three doses and 34 patients in the placebo group.

The two groups were comparable with respect to the relative proportion of knee reconstruction to knee replacement surgery, the age of the patients included, and the duration of the surgery ( Table 1). There were more female than male patients included in both treatment groups (Table 1). The gender ratio was not statistically different between the treatment groups (P = 0.89 Yates corrected {chi}2 test). Cumulative morphine consumption for the two groups in the first 24 h postoperatively is shown in Figure 1. The dextromethorphan-treated patients took less morphine from the PCA machine and the curves for cumulative morphine consumption in the two groups diverged progressively during the first 24 h postoperatively. The total morphine consumption (mg per patient) at the 24-h period was 52.6 ± 5 (mean ± SEM, n = 34) for the placebo-treated patients and 37.2 ± 7.4 (mean ± SEM, n = 22) for the dextromethorphan-treated patients. This difference in morphine consumption of 29.3% is statistically significant (P < 0.05 Student’s unpaired t-test). The morphine usage mean and SD in the control group were very similar to those used for the power analysis (17)


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  		Table 1. Gender Ratio, Age, and Duration of Surgery for Patients Treated with Placebo and Dextromethorphan
 


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  		Figure 1. Bar graph showing cumulative morphine consumption for placebo- (diamonds) and dextromethorphan- (triangles) treated patients. Values shown are means and bars ± SEM. At 24 h dextromethorphan treated patients had used significantly less morphine (P < 0.05, Student’s t-tests).

 
The VAS for the two groups are shown in Table 2 as medians and interquartile ranges for the measurements taken postoperatively at 2, 4, 6, 8, 12, 16, 20, and 24 h after test medication administration. There were no significant differences between the two groups with respect to VAS for pain that were measured on movement because all of the patients included in the study maintained physiotherapy on the CPM machine for the full 24 h. The same conclusion was drawn when the verbal rating scales for pain were analyzed. This is shown in Table 3. The total number of verbal rating scores of 0, 1, 2, or 3 reported between 2 and 24 h postoperatively for placebo-treated and dextromethorphan-treated patients were entered into a contingency table (Table 3). This was subjected to {chi}2 analysis that showed no significant differences between the groups in postoperative pain experience on movement with the CPM machine using verbal rating scales as the measure.


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  		Table 2. Visual Analog Scores (VAS) for Pain on Moving 2–24 h After the First Dose of Dextromethorphan or Placebo
 

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  		Table 3. Verbal Rating Scores for Movement-Associated Pain
 
Similar contingency table analyses were performed for all of the measurements of postoperative side effects. Only the measurements of nausea proved to be of statistical significance. The total number of nausea rating scale scores for the time period 2–24 h are shown in Table 4. Dextromethorphan treatment caused a significant increase in nausea scores. One patient in the dextromethorphan group experienced mild hallucinations at one time point only.


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  		Table 4. Verbal Rating Scores for Nausea
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
There is good evidence from the basic scientific literature to believe that acute postinjury pain states in humans could be treated usefully with a combination of opioids and NMDA antagonists (20–22). This theory has been used to great effect in the use of small dose ketamine in combination with morphine to decrease secondary hyperalgesia and postoperative pain experiences, including movement-associated pain (3,7). There is no oral preparation of ketamine. Unfortunately, drug discovery programs directed toward the development of an oral drug with an acceptable side effect profile have produced no modern candidate. Thus, it was of some interest when it was discovered that dextromethorphan, a compound available over the counter for the suppression of cough, was found to be a weak, noncompetitive NMDA antagonist in rats (8,23,24).

Rather large doses of dextromethorphan have been used in animals to demonstrate these effects on central sensitization. No dose-response relationship for this effect has been investigated in humans. The usual antitussive dose that is well tolerated with minimal side effect is 15–20 mg four to six hourly in an average adult. A dose escalation study has been performed to investigate possible neuroprotective effects in neurosurgical patients (also a property of NMDA antagonists in animals). That dose escalation study reported that patients tolerated a dose up to 400 mg every six hours. However, those patients were not receiving any other central nervous system depressants as would postoperative patients and the incidence of side effects was very frequent–42% suffering from dose-related side effects such as nystagmus, dysarthria, visual disturbances, nausea, and vomiting (25). Thus the clinical trials investigating the analgesic effects of dextromethorphan have used a variety of doses with no knowledge of the dose-response relationship for dextromethorphan as an NMDA antagonist.

Results from experiments in experimental pain have varied. A small dose of dextromethorphan decreases temporal summation caused by a repetitive noxious heat stimulation of the thenar eminence (12). However, another study of pain intensity and unpleasantness induced by experimental ischemia and topical capsaicin failed to reveal any antinociceptive effects of 100 or 200 mg of dextromethorphan given orally. However, it was noted in the latter study that 200 mg was associated with marked side effects (26).

Results from studies of the use of dextromethorphan in postoperative pain are similarly varied. A small dose of dextromethorphan improves postoperative experiences after tonsillectomy and laparoscopic cholecystectomy (27,28). However, when one considers previous work in which the surgery was more extensive, the results are less convincing (15,29). In all of these studies there was no report of significant reduction in the pain experienced with movement and no or minimal opioid sparing (30%).

From the above discussion, we can conclude that the results predicted by the animal work demonstrating NMDA antagonist properties of dextromethorphan plus the work on experimental pain in humans that demonstrates changes in measures of central summation do not seem to have been realized in clinical trials of postoperative pain with major surgery. Because there were no reports of improvement of the pain experience associated with movement, one cannot conclude that any drug effects reported were because of NMDA antagonist properties of dextromethorphan. Clearly this could result from an inadequate dose being given in previous studies. This reasoning led to the trial reported in this article.

A maximum tolerated dose had not been defined in the postoperative population consuming opioids for postoperative pain relief. This was the reason for the first part of the study, which gave a clear result i.e., that a dose of 750 mg could be given at one time. However, when the full trial was started, 50% of the patients experienced severe pruritus or nausea after the initial 400-mg dose. This necessitated a further dose reduction in this patient population. Despite this, the results show clearly that 200 mg of dextromethorphan given eight hourly still leads to a significant increase in postoperative nausea. We may therefore conclude that the dose of 200 mg dextromethorphan given eight-hourly in this patient population is at the limit of tolerance of patients administering morphine to themselves via PCA for postoperative pain relief. When this drug was administered at this dose in a double-blinded randomized fashion, this study, like others, showed a modest reduction in postoperative morphine consumption (29%) with no other benefit. Despite increasing the dose of dextromethorphan four- to six-fold over other studies, there were no further increases in morphine sparing. There were also no significant changes in postoperative pain experienced on movement of the operated knee. Indeed there was not even a trend to indicate there might be a small effect that would require larger numbers to reach statistical significance. The power analysis for this study indicated that there were sufficient numbers of patients in each group to detect 25% reduction in opioid use and 20 mm reduction in VAS for pain on moving. Although a gender imbalance was not statistically different between the treatment groups, it might still be argued that this made a positive result less likely. However, there are no gender differences for this type of surgery in mean PCA opioid requirements (17). This study, like others before it, has failed to provide any evidence for orally administered dextromethorphan to be acting as an NMDA antagonist in the management of postoperative pain in humans.

Dextromethorphan does possess other pharmacological properties. It is a weak mu opioid agonist with 1/6th to 1/10th the potency of codeine and it is a monoamine reuptake inhibitor 1/20th of the potency of Tramadol for 5HT reuptake and 1/3rd the potency of Tramadol for noradrenaline reuptake (30). These properties might explain the small opioid-sparing effect that reaches a ceiling at 20–30% without any effects on movement-associated pain.

Dextromethorphan is an NMDA antagonist that improves postoperative analgesia only marginally, even at the maximum tolerated dose of 200 mg 8 hourly. The opioid-sparing effect occurs at a cost of increased nausea, and thus we conclude that oral dextromethorphan is not clinically useful in the treatment of postoperative pain after knee surgery.


   Acknowledgments
 
The authors wish to thank FH Faulding & Co. Limited and especially Jane Kelly for logistical support for this study. In addition, many hospital staff gave freely of their time and energy, particularly surgical colleagues, nurses and physiotherapists at the Avenue Hospital, Frankston Hospital, and Monash Medical Center.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication October 2, 2000.




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Preoperative Oral Dextromethorphan Attenuated Tourniquet-Induced Arterial Blood Pressure and Heart Rate Increases in Knee Cruciate Ligament Reconstruction Patients Under General Anesthesia
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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press