Thomas G. Kantor

Response of experimental pain to analgesic drugs: I. Morphine, aspirin, and placebo

Two methods of inducing pain experimentally in man have been investigated as possible laboratory instruments for evaluating analgesic efficiency; one uses electrical stimulation of two fingers, yielding one touch and two pain response parameters, the other, thermal stimulation of the hand by immersion in ice water, yielding three pain response parameters. Sixty paid healthy volunteers were divided into three groups of 20 each. One group received placebo in all four experimental sessions, the second received morphine twice and placebo twice, and the third received aspirin twice and placebo twice. The results indicated significant changes occurring during morphine conditions for both the pain, but not the touch, response parameters produced by electrical stimulation; and for pain tolerance and pain sensitivity range, but not for pain threshold, obtained with ice‐water stimulation. Aspirin failed to produce Significant changes in any response parameter with either technique, but in some subiects lowered the pain threshold. Some laterality differences between the dominant and nondominant hands were observed which were occasionally significant.

A bioassay computer program for analgesic clinical trials

A Fortran program to calculate estimates of relative potency of a test to a standard analgesic is described. The program considers, at the option of the users, four distinct populations: completers, all of those patients who have completed a full crossover round of medication; two‐rounders, patients who have completed two or more rounds of medication; incompleters, patients who have not completed one or more rounds of medication; and first dose only patients, the initial administration received by all patients in the study whether or not they have dropped out. Up to six observations plus the initial reading for pain intensity scores and pain relief scores may be processed separately. The program also creates several summary variables including: SPID, an estimate of the area under the reciprocal of the pain intensity curve; TOTAL, an estimate of the area under the pain relief curve; and estimates of onset and duration as measured by relief scores and by pain intenSity scores. The program automatically performs calculations‐ for the analysis of variance and produces F values when appropriate for testing linearity of the log dose relationship, parallelism of the two curves for test and standard, and so forth. The paper discusses the rationale behind the approach adopted in the program.

Use of diclofenac in analgesia

The inhibition of prostaglandin synthesis by nonsteroidal anti-inflammatory drugs can alleviate the pain and inflammation associated with a variety of disorders. Nonsteroidal anti-inflammatory drugs have a role, therefore, in the treatment of nonrheumatic conditions as well as in the treatment of rheumatic diseases, an area in which these agents have been used and studied more extensively. In clinical conditions marked by acute or chronic pain and inflammation, such as oral surgery, dysmenorrhea, low back pain, renal colic, and biliary colic, as well as in post-traumatic and postoperative conditions, diclofenac sodium, a nonsteroidal anti-inflammatory drug with potent prostaglandin synthetase inhibition, has been shown to be an effective analgesic agent. In the current studies, diclofenac was given orally or by intramuscular injection in doses ranging from 50 to 75 mg daily, or up to 150 mg per day for longer-term use. When compared with placebo, diclofenac provided consistently superior relief of symptoms. Comparisons with other nonsteroidal anti-inflammatory drugs or with opioids, such as pentazocine or Spasmofen, demonstrate that symptom relief with diclofenac was either comparable to or better than that obtained with these agents.

Adverse Effects of Commonly Ordered Oral Narcotics

Abstract: Approximately equianalgesic oral doses of codeine, an oxycodone compound resembling Percodan, and pentazocine were compared for adverse effects in a double‐blind, randomized study of four doses of each drug given over two days to 247 postsurgical patients with pain. Placebo and parenteral morphine were also treated as negative and positive controls, respectively. Approximately 50 patients each received one of the five drugs. Codeine, pentazocine, and morphine had the same incidence of adverse effects (22 to 28 per cent). One capsule of oxycodone compound was the analgesic equivalent of 12.5 mg morphine with an adverse effect incidence of 4 per cent (placebo 8 per cent). Smoking made no difference in analgesic effect or adverse effects. Analgesics given in the evening intervening between the two days may have affected the analgesic performance of placebo.

Response of experimental pain to analgesic drugs. II. Codeine and placebo.

Twenty‐four paid healthy human volunteers participated in a study of two algesimetric methods of measuring experimental pain, one employing cutaneous electrical stimulation of two fingers with one touch and two pain response parameters, the other utilizing immersion of the hand in ice water, yielding three pain response parameters. A double‐blind balanced randomized block design was used. Both permissive and nonpermissive instructions were employed with the electrical stimulation. It was found that tolerance to experimental pain consistently increased significantly with codeine for both methods and with both sets of instructions. On the other hand, codeine exerted a smaller and only occasional significant effect on pain threshold.

A Double‐Blind Parallel Comparison of Ketoprofen, Codeine, and Placebo in Patients with Moderate to Severe Postpartum Pain

Abstract: A total of 152 patients were treated at a single center in a single‐dose, double‐blind parallel study designed to compare the safety and efficacy of 25, 50, and 100 mg ketoprofen to 90 mg codeine and placebo in patients with moderate to severe postpartum pain (i.e., postepisiotomy, uterine cramping, or cesarean section pain). The analgesic responses to all three doses of ketoprofen and 90 mg codeine were superior to placebo and were not significantly different from each other. No dose‐related response was observed with ketoprofen. The number of side effects was significantly greater (P = 0.001) among patients receiving codeine (six patients) than among those receiving ketoprofen (three patients).

Management of cancer pain with oral controlled-release morphine sulfate.

Morphine sulfate Contin (MSC) is an investigational matrix delivery system for oral morphine sulfate that allows for prolonged blood levels of morphine. Twenty‐six patients with inadequately controlled cancer‐related pain were examined in an open but controlled study using MSC. Initially, all patients were converted from the prestudy analgesic regimen to an equianalgesic amount of immediate‐release morphine sulfate (IRMS) on a q4h dose schedule that was in turn titrated to the level of adequate pain relief. Patients then were switched to MSC q8h and eventually to q12h, starting at doses representing the same total daily amount of morphine that was in the final IRMS dose. Of the 18 patients who completed the study, all achieved satisfactory levels of analgesia on MSC, seven at q8h and 11 at q12h dosing intervals. All patients reported better analgesia while taking MSC compared with their previous regimen. Side effects associated with MSC included sedation and constipation but not nausea or respiratory difficulty. Significant drug tolerance did not develop during a mean follow‐up period of four weeks (range, 1–18 weeks). MSC is an effective oral opioid analgesic that allows an increased dose interval without increased side effects or decreased potency. It can improve the quality of life of cancer patients by allowing them to be maintained without frequent dosing or parenteral medication.

Bradykinin as a Mediator of Human Pain.

Summary In man, the polypeptides brady-kinin and kallidin, but not eledoisin, produce pain on intraperitoneal injection. None of these substances produces pain when injected subcutaneously or intramuscularly in higher concentrations. Therefore, none of these polypeptides can be considered as a universal mediator of pain.

Concepts in pain control

T A MEETING OF rheumatologists at McA Master University in 1981, break-out groups were asked what the arthritic patient particularly demanded of the doctor. Each group agreed that the answer was “relief from pain.“’ Given the knowledge available at present, relief from pain for the patient with arthritis is well within the reach of each practitioner. In this article, the emphasis is on pharmacological measures for the relief of pain, but other physical measures will also be described. To begin, however, present conceptions of the neurological basis of pain and pain apperception will be reviewed, with emphasis on rheumatic problems.

Current modalities in arthritic diseases

Little progress has been made in identifying the etiologies of the major rheumatologic diseases, which substantially limits our ability to identify truly disease-modifying treatments. Despite this constraint, major advances in the suppression of the signs and symptoms of these diseases have been made. Second-line drugs such as methotrexate have gained wide acceptance among rheumatologists and may supplant gold as the major therapy for rapidly advancing rheumatoid arthritis. The nonsteroidal anti-inflammatory drugs (NSAIDs), however, remain the first line of treatment for arthritic conditions. In recent years, much has been learned about how the NSAIDs suppress the inflammation and pain of arthritis. Even here, however, several inconsistencies exist with our current understanding. New findings in neurobiology may shed light on some of these puzzling features. Although the number of NSAIDs currently available seems a bit overwhelming, rationale exists for their continued development. Many patients do not have a response to some or all of these agents, with noncompliance because of gastrointestinal intolerance being among the probable causes. New compounds that offer improved safety in this regard are greatly needed.