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In a double-blind placebo-controlled study we investigated the analgesic efficacy of combinations of the serotonergic tricyclic antidepressant fluoxetine with either the mu-opiate morphine or the kappa-opiate pentazocine. Administration of oral fluoxetine (10 mg p.o. daily for 7 days pre-operatively) had no effect on the immediate postoperative pain level. However, pre-operative administration of fluoxetine was found, compared to placebo, to antagonize analgesia seen after administration of morphine (6 mg, i.v.) in the immediate postoperative period. Attenuation of morphine analgesia consisted essentially of a shortening of the duration of action of the dose of morphine administered. Similar administration of fluoxetine had no effect on the analgesia produced by the kappa-opiate pentazocine (45 mg, i.v.). This effect probably results from alteration in the known serotonergic circuits in endogenous pain-modulating systems.

Administration of desipramine, the tricyclic noradrenergic agent, for 7 days pre-operatively, had been found to potentiate postoperative morphine analgesia. In this study we investigated the necessary timing of administration of desipramine in its action to potentiate morphine analgesia. We report that the administration of desipramine for only 3 days, starting 7 days before surgery, also potentiated postoperative morphine analgesia and that the analgesia observed was not different from that in patients receiving a full 7 days of desipramine pre-operatively. The potentiation of morphine analgesia observed was most evident as a prolongation of the analgesic response. Patients who also received desipramine for only 3 days, but starting 3 days pre-operatively had an analgesic response to postoperative morphine that was the same as that in patients receiving placebo. The ability of the administration of desipramine early in the pre-operative week to interact with postoperative morphine and the lack of response when desipramine was given late in the week does not have an explanation at present. However, it may reflect the known latency in humans to the onset of the central effects of tricyclic antidepressants (TCAs).

Opiate-adrenergic interactions were investigated by studying the effect of the selective alpha2-adrenergic agonist, clonidine, on the analgesia produced by intravenous placebo and by the predominantly kappa-opiate agonist, pentazocine, in patients with dental postoperative pain. Clonidine did not affect the pain level when administered with intravenous placebo. When administered with pentazocine, clonidine caused a statistically significant increase in pentazocine analgesia. Comparison is made to other opiate-adrenergic interactions and possible mechanisms are discussed.

Nalbuphine, pentazocine, and butorphanol, mixed agonist/antagonist opioids that induce analgesia by acting predominantly at kappa opioid receptors, have recently been shown in single-dose studies to have greater analgesic efficacy in women than in men. In the current experiments, the first placebo controlled dose response study of opioid analgesic efficacy that examines for gender differences, nalbuphine (5, 10, or 20 mg) and placebo were evaluated in 62 men and 69 women for the treatment of moderate to severe postoperative pain following extraction of impacted wisdom teeth. In a randomized, open injection, double blind experimental design, pain intensity was recorded on a 10 cm visual analog scale (VAS) immediately prior to drug administration (baseline) and at 20 min intervals thereafter. Although responses to placebo were similar in men and women, for all doses of nalbuphine women exhibited significantly greater analgesic response than men, compatible with our previous results. Unexpectedly, men receiving the 5 mg dose of nalbuphine experienced significantly greater pain than those receiving placebo; only the 20 mg dose of nalbuphine in men produced significant analgesia compared to placebo. While a similar antianalgesic effect was not observed in women, only the 10 mg dose of nalbuphine produced significant analgesia compared to placebo. These results suggest that the optimal analgesic dose of nalbuphine for women is lower than the highest dose that can be safely administered. In contrast, the antianalgesic effect of nalbuphine suggests avoidance of its routine use for postoperative analgesia in men until further studies clarify this issue. Because gender differences in other mixed kappa agonists/antagonists (i.e. pentazocine and butorphanol) have previously been shown, these results may generally apply to this class of opioid analgesics.

Activation of supraspinal gamma-aminobutyric acid-A (GABAA) receptors is known to result in antagonism of opioid analgesia. Since benzodiazepines enhance the action of GABA at GABAA receptors, we hypothesized that administration of these agents for preoperative sedation might antagonize the analgesic effects of opioids administered postoperatively. If so, then administration of the benzodiazepine antagonist flumazenil should enhance postoperative morphine analgesia. In a double-blind, placebo-controlled study of patients who received a preoperatively administered benzodiazepine (diazepam) for sedation and a postoperatively administered opioid (morphine) for analgesia, we investigated opioid-benzodiazepine interactions affecting postoperative dental pain. We found that flumazenil significantly enhanced morphine analgesia consistent with the hypothesis that the preoperatively administered benzodiazepine exerts an ongoing antianalgesic effect. In addition, we followed these patients over the first and second postoperative days to determine if there were differences between the drug groups in post-discharge pain, analgesic consumption, or side-effects. Participants receiving flumazenil reported significantly less post-discharge nausea and used significantly less ibuprofen. Since post-discharge pain levels were not significantly different, these results suggest that the patients receiving flumazenil required less analgesic medication to achieve a comparable level of pain control. In summary, our results indicate that the benzodiazepine antagonist flumazenil enhances morphine analgesia and decreases post-discharge side-effects as well as post-discharge need for analgesic medication.

Opiate-adrenomimetic interaction was investigated by studying the effect of the adrenomimetic agent, ephedrine, on the analgesia produced by intravenous placebo and that produced by the predominantly kappa opiate agonist, pentazocine, in patients with dental postoperative pain. Ephedrine did not significantly affect the analgesia of intravenous placebo or of pentazocine. These results contrast with earlier studies demonstrating enhancement of opiate analgesia by other adrenomimetics. Further clinical studies are needed to delineate the specificity of opiate-adrenomimetic interaction.

In 30 patients with dental postoperative pain we tested the hypothesis that the analgesic effects of nitrous oxide (N2O), a mild analgesic, may be mediated via endogenous opioids. Using the visual analog scale to assess pain, significant analgesia was induced by 33% N2O. N2O-induced analgesia was not significantly antagonized by 10 mg of intravenous naloxone. In the setting of clinical pain there appears to be little if any contribution of endogenous opioids to N2O-induced analgesia.

Heart rate response to physiologic maneuvers was used to evaluate autonomic nervous system (ANS) function in normal control subjects and during the stress and pain experienced by patients before and after surgery. In preoperative patients (stressed without pain) and postoperative patients (stressed with pain), maneuvers which routinely increase activity in the parasympathetic or sympathetic divisions of the ANS produced only 50% of the response seen in control subjects. The heart rate response was not further reduced in patients with pain compared to patients with stress alone. The difference in heart rate response between surgical patients and control subjects was not accompanied by a difference in baseline heart rate. The data suggest that tonic stress impairs the ability of the ANS to respond fully to perturbing influences.

We used certain physiologic maneuvers to perturb the autonomic nervous system (ANS) in an attempt to detect a link between the ANS and pain. In the unperturbed state, we found no difference in the electrodermal response among normal controls, preoperative patients (increased stress without pain) and postoperative patients (increased stress and pain). The electrodermal response elicited by autonomic maneuvers was significantly attenuated in postoperative patients but not in preoperative patients or in normal control subjects.

The effects of placebo and varying doses of intravenous morphine were studied in 74 patients. All patients underwent extraction of impacted mandibular third molars. Two hours after onset of anesthesia all patients received a placebo (intravenous saline). One hour after the placebo administration each patient received either a second placebo or, 4, 6, 8 or 12 mg of morphine, double blind, via a hidden intravenous line. Pain level was evaluated 50 min after morphine administration using a visual analog scale. Pooled data from all patients produced a dose-response curve asymptotic by 8 mg. The mean pain relief following the second placebo was found to be between that obtained following hidden administration of 4 and 6 mg of morphine. When pain level reports for individuals were plotted two unexpected features appeared. First, no patient reported complete relief, even at the highest dose of morphine (12 mg). Second, pain level reports 50 min following each dose of morphine tended to be in two clusters. Within each cluster the average pain was independent of the dose of morphine administered. However, in groups receiving progressively higher doses of morphine, the percentage of patients within the low pain level cluster increased. These latter observations are most consistent with the concept that there is a step component for narcotic analgesia.

In a double-blind, placebo-controlled study the analgesic efficacy of the combination of a tricyclic antidepressant and morphine was investigated. One of two tricyclic antidepressants (either amitriptyline, a relatively selective serotonin uptake inhibitor or desipramine, a relatively selective noradrenaline uptake inhibitor) or a placebo, was given for 1 week prior to surgery, followed by a single postoperative dose of morphine. Desipramine, but not amitriptyline, both increased and prolonged morphine analgesia. Neither tricyclic antidepressant reduced dental postoperative pain in the absence of morphine. We propose that desipramine enhances opiate analgesia by enhancing a noradrenergic component that contributes to endogenous opioid-mediated analgesia systems.