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© 1999 International Anesthesia Research Society
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Abstract |
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We studied the effect of dextromethorphan, an N-methyl-D-aspartate antagonist, on analgesic consumption and pain scoring after abdominal hysterectomy. In this double-blinded study, 50 patients were randomized into two groups. Group DM was given oral dextromethorphan 40 mg with their premedication, then 40 mg three times per day for the next 2 days. Group P received placebo at identical times. Postoperative analgesic requirements were assessed using a patient-controlled analgesia system and subsequent oral analgesic intake using a set protocol. Pain was assessed at rest and on movement using a visual analog scale 4, 24, 48, and 72 h after the operation. Median pain scores at rest were significantly lower at 48 and 72 h and also for the sum of all resting pain scores. Mean morphine consumption was less in Group DM (1.1 vs 1.5 mg/h; P = 0.054). Usage of oral diclofenac, given every 8 h as needed, did not differ between groups, but consumption of codydramol (paracetamol 500 mg and dihydrocodeine 10 mg) was significantly less in Group DM. We conclude that the use of oral dextromethorphan has an analgesia-sparing effect and some beneficial effects on pain scoring at rest after abdominal hysterectomy.
Implications: Patients given dextromethorphan before and after surgery had a significant reduction in some pain scores at rest, but not on movement. There was a trend to lower morphine requirements in the first 24 h. Over the next 48 h, oral analgesic usage was significantly reduced.
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Introduction |
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Major advances in our understanding of neurophysiology have brought us the concept of a "plastic" central nervous system (CNS) that can not only adapt to incoming stimuli, but also modulate signal transmission (1). Animal models have given rise to the theory of central hypersensitivity. In prolonged, severe acute pain, a constant nociceptive barrage is transmitted centrally to the spinal cord via peripheral nerves. If the stimulus is of sufficient duration and intensity, it sensitizes the dorsal horn neurons. The resultant lower threshold for firing leads to central hypersensitivity (or "wind-up") and an enhanced response to a given painful stimulus.
Glutamate is the principle excitatory neurotransmitter in the CNS. Many peripheral sensory fibers, including the C fibers, which convey pain, contain glutamate in addition to neuroactive peptides, such as substance P. There are three main receptors for glutamate on the dorsal horn nociceptive neurons: 
-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), metabotropic, and N-methyl-D-aspartate (NMDA) (2). The AMPA receptor seems to set the baseline level of nociception and faithfully transmits the intensity and duration of peripheral stimulus. In "normal" activity in pain circuits, the NMDA receptor is inactive. However, if the pain stimulus is sustained and intense, sufficient quantities of peptides and glutamate are released; they then act in concert to activate the NMDA receptor. Once activated, ions (mainly calcium) flow through the receptor channel, causing massive neuronal depolarization and greatly increased excitability of the neuron. It is through this mechanism that central hypersensitivity is thought to be mediated (3).
Dextromethorphan, the D-isomer of the codeine analog levorphanol, is widely used for its central antitussive action. It has weak affinity (one-tenth that of codeine) for the µ-opioid receptor (4). In the adult antitussive dose range (up to 120 mg/d), it has no analgesic or sedative effects, nor is it a respiratory depressant. In addition, it is a noncompetitive antagonist at the NMDA receptor. This property has led to its experimental use in a number of clinical areas, such as acute (5–7) and chronic pain (8) and neuroprotection after brain injury (9).
The aim of our study was to examine the effect of dextromethorphan on postoperative pain by assessing its effect on both analgesic requirements and pain scoring after abdominal hysterectomy.
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Methods |
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After obtaining written, informed consent and approval of the local hospital ethics committee, we studied, in double-blinded fashion, 50 women aged 30–60 yr, ASA physical status I or II, undergoing elective total abdominal hysterectomy. Patients were excluded if they were unable to give informed consent, were taking regular oral analgesic medication, or had a contraindication to receiving any of the study drugs. A Doctors and Dentists Exemption Certificate was obtained from the Medicines Control Agency for this unlicensed use of dextromethorphan (Roche Products, Derbyshire, UK).
Computer-generated randomization allocated patients to Group DM (dextromethorphan) or Group P (placebo). Group DM was given 40 mg of oral dextromethorphan with their premedication (90 min before surgery), 40 mg on the evening after surgery, and then 40 mg three times per day for the next 2 days. Group P was given placebo capsules (lactose) at identical times. The study drugs were prepared by the hospital pharmacy.
All patients were premedicated with 20 mg of oral temazepam 90 min before the operation. Monitoring (electrocardiograph, pulse oximeter, and noninvasive blood pressure) and IV access were established in the anesthetic room. General anesthesia was induced with propofol (2–3 mg/kg) and fentanyl (1.5 µg/kg). Neuromuscular block was established with atracurium (0.5 mg/kg), and the patients’ tracheas were intubated. The lungs were ventilated to normocapnia (end-tidal carbon dioxide tension 30–35 mm Hg), and anesthesia was maintained with 70% nitrous oxide in oxygen and enflurane (1%–3%). During surgery, the patients were given IV morphine titrated to a total of 0.15 mg/kg and 0.5 mg of droperidol IV. At the end of the procedure, the abdominal wound was infiltrated with 15 mL of 0.5% plain bupivacaine, and the patient was given 100 mg of rectal diclofenac. This was recorded as time 0. Patients also received augmentin 1.2 g, neostigmine 2.5 mg, glycopyrrolate 0.5 mg, and 1 L of lactated Ringer’s solution during the operative period.
After the operation, IV morphine was self-administered via a patient-controlled analgesia (PCA) pump programmed to deliver a 1-mg bolus of morphine with a 5-min lockout and no background infusion. The morning after surgery, the PCA morphine pump was stopped and replaced with on-demand oral analgesia. Diclofenac 50 mg every 8 h on request was the default analgesic, but if <8 h since last diclofenac administration, two tablets of oral codydramol (paracetamol 500 mg and dihydrocodeine 10 mg) were given. Antiemetics were given as required.
IV morphine and oral analgesic consumption were charted for all patients. The PCA chart also recorded hourly scores for respiratory rate, and nurses assessed sedation using a 4-point scale (0 = alert, orientated; 1 = occasionally drowsy; 2 = frequently drowsy; and 3 = unrousable). Assessment of postoperative pain at rest and on movement (from supine to sitting in bed) was made at 4, 24, 48, and 72 h using a 100-mm visual analog scale (VAS; 0 = no pain to 100 = worst pain imaginable). Any side effects were noted at these time points and on the PCA chart. Patients were specifically questioned with regard to symptoms of nausea, vomiting, dizziness, and gastrointestinal upset.
Demographic data and analgesic usage were analyzed by using Student’s t-tests. VAS pain scores underwent Mann-Whitney analysis with Bonferroni correction. P < 0.05 was considered significant. A previous study at our institution (10) indicated a mean total morphine consumption of approximately 34 ± 20 mg/d. We decided that a decrease in usage to <20 mg/d would be clinically significant (i.e., an approximately 40% reduction in morphine usage). With an error of 0.05, 48 patients were required to achieve a power of 90% for the study (11).
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Results |
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Fifty patients were recruited to the study. Three patients were excluded: one who developed a wound hematoma and was not given diclofenac (Group P), and two for whom incomplete data were recorded (one in Group DM, one in Group P). There were 24 patients in the dextromethorphan group. Their mean (± SD) age was 44 ± 8 yr, height 163 ± 6 cm, and weight 67 ± 12 kg. The placebo group consisted of 23 patients with a mean age of 42 ± 10 yr, height 162 ± 7 cm, and weight 72 ± 11 kg.
Median VAS pain scores at rest were lower in Group DM at all time points, reaching statistical significance at 48 h (15 vs 22) and 72 h (9 vs 18). The sum of all resting pain scores (i.e., integrating the pain experience over the first 3 days) was also significantly lower in Group DM (median score 75.5 vs 124.5; P < 0.01). There was no significant difference in pain scores on movement at any of the time points (Table 1). The sum of all pain scores on movement also produced no significant difference between Groups DM and P (167.5 vs 213.5).
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In the first 24 h, the mean amount of PCA morphine used was greater in Group P versus Group DM (1.5 vs 1.1 mg/h), although this did not reach statistical significance (P = 0.054).
Over the next 48 h, Group DM used significantly less codydramol (10.6 vs 15.1 tablets), but there was no difference in diclofenac usage between the two groups (Table 2).
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There was a higher incidence of nausea and vomiting in Group P (Table 3). Dizziness was uncommon (two patients in Group DM, one patient in Group P). There was no difference in sedation scoring between the groups. Of the patients, 90% had a maximal sedation score of 1 or 2 on the 4-point scale. No patients exhibited excess sedation in either group.
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Discussion |
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Our study shows that NMDA antagonists such as dextromethorphan may have a supportive role in postoperative pain control.
Dextromethorphan was well tolerated, with no difference in recorded side effect profiles compared with placebo. This is in agreement with the side effect profile recorded by McConaghy et al. (6), although they administered a smaller dose of dextromethorphan. Because of the small number of patients who received the study drug, it is difficult to give a definitive answer to the side effect profile when dextromethorphan is used in combination with postoperative analgesia.
NMDA receptor antagonists block or attenuate signal transmission in one of the major excitatory neurotransmitter systems within the CNS. This property has led to investigation of their effects in areas such as acute and chronic pain and neuroprotection after brain injury. In acute pain, evidence of potential benefit has accumulated in both animal and human volunteer work.
Woolf and Thomson (3) demonstrated in rats that the induction and maintenance of central hypersensitization is dependent on NMDA receptor activation. They then successfully used competitive (D-CPP) and noncompetitive (MK-801) NMDA receptor antagonists to prevent central hypersensitization. More recently, Plesan et al. (12) compared two clinically available NMDA antagonists, ketamine and dextromethorphan. The ability of these drugs to potentiate the antinociceptive effects of morphine in rats was examined using the hotplate model of acute pain. Dextromethorphan was more effective than ketamine in enhancing the analgesic effects of morphine, and it produced its effects at dose levels that, by themselves, did not produce any analgesic effect.
The lack of any analgesic effect on acute pain has also been found in human volunteer studies. Kaupilla et al. (13) gave volunteers 100 mg of oral dextromethorphan. This had no significant effect on pain intensity in response to ischemia or topical capsaicin, nor did it increase the threshold for heat or mechanical pain. Price et al. (14) administered 15, 30, and 45 mg of oral dextromethorphan to volunteers who rated intensities of first (immediate pricking-type pain) and second pain (subsequent burning, aching, throbbing-type pain) in response to repeated painful electric shocks and pulses of heat. Pain scores for both first and second pain were unaffected by any of the doses. However, 30 and 45 mg were effective in attenuating temporal summation of second pain, a psychophysical correlate of wind-up.
The clinical evaluation of NMDA antagonists in acute pain has involved three compounds: magnesium, ketamine, and dextromethorphan. Studies involving magnesium (15) have shown no benefit, unlike those involving ketamine (16). However, the side effect profile of the latter remains unattractive.
Dextromethorphan has been used successfully as an analgesic adjunct in the management of postoperative pain. Kawamata et al. (5) studied 36 adults undergoing tonsillectomy. They were given oral dextromethorphan (30 or 45 mg) or placebo with their premedication. The dextromethorphan 45 mg group had significantly lower pain scores at rest and on swallowing up to six days postoperatively. Statistical significance was also reached in longer time to first analgesic request and total dose of analgesic used.
In our study, we investigated patients undergoing hysterectomy. Two studies have also involved intraabdominal surgery. McConaghy et al. (6) administered two doses of dextromethorphan 27 mg preoperatively, then a further three doses in the first 24 hours postoperatively. They found no difference in VAS pain scoring, PCA morphine consumption, or secondary hyperalgesia (as assessed by using von Frey hairs). However, the dose of dextromethorphan was significantly smaller and was given for a shorter period of time than in our study. Grace et al. (7) administered two doses of dextromethorphan 60 mg preoperatively, then assessed intra- and postoperative morphine consumption and pain scoring. They found a statistically significant reduction in intraoperative morphine requirement but no difference in postoperative analgesic use or pain scoring. We administered the dextromethorphan both pre- and postoperatively for 48 hours in an attempt to counter the continuing nociceptive afferent input into the spinal cord from the surgical wound. Our findings were similar to the tonsillectomy group (5), with lower pain scores at rest and reduced analgesic consumption. These improvements did not come at the expense of increased side effects.
We postulated that dextromethorphan exerts its effect via noncompetitive blockade of the NMDA receptor. Alternative possibilities include µ-opioid receptor potentiation, even at the low levels involved with this dose of dextromethorphan, or a sedative effect. It is possible that the addition of sedative drugs to analgesics could have a beneficial effect on pain scoring through anxiolysis. In our study, we used 40 mg of dextromethorphan every 8 hours for 48 hours and did not detect excess sedation in the study group. This finding is confirmed by studies examining the neuroprotective effects of dextromethorphan in cerebral ischemic injury. Steinberg et al. (9) performed a dose-escalating study in 181 neurosurgical patients who were given 10–400 mg every six hours. No side effects were observed in patients receiving <2.11 mg · kg-1 · 6 h-1. At the dose used in our study, it is unlikely that sedation was responsible for the reduction in pain scoring and analgesic consumption.
Currently, the "gold standard" for postoperative pain management is multimodal analgesia. A study has shown that preemptive application of this technique in clinical practice has met with little success (10). A possible reason for this failure is the inability to provide the degree and duration of analgesia required to prevent wind-up during or after major surgery. We showed that the addition of an NMDA receptor antagonist to our armamentarium holds promise, perhaps by reducing wind-up, thus bringing us closer to our goal of better short- and long-term pain control after surgery. Dose-finding studies with greater power will determine the true value of this drug in postoperative pain management.
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Acknowledgments |
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We thank the medical and nursing staff of the gynecology unit for their assistance in the completion of this study.
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Footnotes |
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Presented in part at the 1998 annual meeting of the European Society of Regional Anesthesia, Geneva, Switzerland.
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References |
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- Woolf CJ. Evidence for a central component of postinjury pain hypersensitivity. Nature (Lond) 1983;306:686–8.[Medline]
- Dickenson AH. NMDA receptor antagonists: interactions with opioids. Acta Anaesthesiol Scand 1997;41:112–5.[Web of Science][Medline]
- Woolf CJ, Thompson SW. The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation: implications for the treatment of post-injury pain hypersensitivity states. Pain 1991;44:203–9.
- Raffa RB. A novel approach to the pharmacology of analgesics. Am J Med 1996;101:40–6S.
- Kawamata T, Omote K, Kawamata M, Namiki A. Premedication with oral dextromethorphan reduces postoperative pain after tonsillectomy. Anesth Analg 1998;86:594–7.[Abstract]
- McConaghy PM, McSorley P, McCaughey W, Campbell WI. Dextromethorphan and pain after total abdominal hysterectomy. Anaesth 1998;81:731–6.
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Grace RF, Power I, Umedaly H, et al. Preoperative dextromethorphan reduces intraoperative but not postoperative morphine requirements after laparotomy. Anesth Analg 1998;87:1135–8.
[Abstract/Free Full Text] - McQuay HJ, Caroll D, Jadad AR, et al. Dextromethorphan for the treatment of neuropathic pain: a double-blind randomised controlled crossover trial with integral n-of-1 design. Pain 1994;59:127–33.[Web of Science][Medline]
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Espinet A, Henderson DJ, Faccenda KA, Morrison LMM. Does pre-incisional thoracic extradural block combined with diclofenac reduce postoperative pain after abdominal hysterectomy? Br J Anaesth 1996;76:209–13.
[Abstract/Free Full Text] - Gore SM, Altman DG. Statistics in practice. 5th ed. Torquay:The Devonshire Press, 1989.
- Plesan A, Hedman U, Xu X-J, Wiesenfeld-Hallin Z. Comparison of ketamine and dextromethorphan in potentiating the antinociceptive effect of morphine in rats. Anesth Analg 1998;86:825–9.[Abstract]
- Kaupilla T, Gronroos M, Pertovarra A. An attempt to attenuate experimental pain in humans by dextromethorphan, an NMDA receptor antagonist. Pharmacol Biochem Behav 1995;52:641–4.[Web of Science][Medline]
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- Wilder-Smith CH, Knopfli R, Wilder-Smith OHG. Perioperative magnesium infusion and postoperative pain. Anaesthesiol Scand 1997;41:1023–7.
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