Mild Analgesics Research Articles

Analgesic Efficacy of Dextropropoxyphene and Dextropropoxyphene-containing Combinations: a Review

Twenty years ago, as part of a review of the clinical pharmacology of mild analgesics (Beaver, 1965, 1966), I evaluated reports of those analgesic trials of dextropropoxyphene that appeared to satisfy the minimum methodologic requirements for a controlled clinical trial of analgesic efficacy. On reviewing reports of studies that have been published since then, I find little need to modify my evaluation of the efficacy of dextropropoxyphene that appeared in 1966, at least in respect to the effect of single oral doses: In summary, dextropropoxyphene (hydrochloride) is a mild oral analgesic which has proven superior to placebo in doses of 65 mg or more but which is of questionable efficacy in doses lower than 65 mg. The drug is definitely less potent than codeine: the best available estimates of the relative potency of the two drugs indicating that dextropropoxyphene is approximately 1/2-2/3 as potent. Likewise, dextropropoxyphene in 32-65 mg doses is certainly no more, and possibly less, effective than the usually used doses of aspirin or A.P.C. (aspirin/phenacetin/caffeine). In the interim, the efficacy of dextropropoxyphene has been the subject of a number of other critical reviews (Miller et al., 1970; Miller, 1977), commentaries (Kiplinger & Nickander, 1971; Lasagna, 1976), and even congressional hearings (Beaver, 1979; Moertel, 1979). More importantly, new controlled clinical trials involving dextropropoxyphene hydrochloride or napsylate have been reported, and some of these use more sophisticated design and analysis than those available in 1966. I will therefore discuss the results of those newer studies of apparently suitable scientific design that meet at least the minimum criteria for a valid clinical assay of analgesic activity (Beaver, 1965; Houde et al., 1965,1966; Wallenstein & Houde, 1975; Beaver, 1983), and I will comment on only a few of the studies included in my previous review (Beaver, 1966).

Treatment of tumor pain

The management of pain in cancer patients requires experience and a therapy-protocol. Analgesics should be given orally and on a fixed schedule. Necessary is a cascade which allows a stepwise escalation. Patients should be treated with mild analgesics first and continuous infusions of narcotics may be used in the final stage of cancer. The combination of analgesic and psychopharmacological agents augments the analgesic effect. Quite often the side effects of analgesic therapy require an individual schedule.

The treatment of upper extremity reflex sympathetic dystrophy with prolonged continuous stellate ganglion blockade

Twenty-nine consecutively treated patients over a 5-year period with upper extremity reflex sympathetic dystrophy were admitted to Massachusetts General Hospital for prolonged continuous stellate ganglion blockade. Diagnosis was based on the presence of pain, decreased joint motion, trophic changes, and vasomotor disturbances. Selection for blockade was made on the failure to improve with outpatient physical therapy, tranquilizers, and mild analgesics. Treatment consisted of indwelling-catheter injections of bupivacaine hydrochloride every eight hours to the stellate ganglion for an average of 7 days, supplemented with vigorous physical therapy. Improvement during treatment was documented in all but two patients with regard to pain and decreased joint motion and in two-thirds with regard to trophic and vasomotor changes. Long-term follow-up demonstrated a relapse rate of 25%, but marked improvement persisted in the rest and normal status was attained in four of 26 patients at an average of 3 years later.

The use of non-prescription analgesics in an older population.

Older patients are frequent users of aspirin and acetaminophen, either recommended by physicians or self-prescribed, for the aches and pains that accompany aging. These mild analgesics provide effective pain relief when used appropriately. Aspirin and acetaminophen are equianalgesic on a milligram-for-milligram basis for most indications. Both are safe for most patients. Aspirin use may be associated with salicylate intoxication or salicylate interactions with other agents. There have been reports of an association of hepatotoxicity with acute massive overdosages of acetaminophen.

Reflex Sympathetic Dystrophy in Children

Six patients with reflex sympathetic dystrophy were investigated during the period between 1973 and 1978. Children do not develop the severe, disabling pain nor the patchy osteoporosis (Sudeck's atrophy) which are considered essential features of reflex sympathetic dystrophy in adults. In contrast to the adult variety, reflex sympathetic dystrophy in children is a self-limiting condition which usually responds well to mild analgesics and physical therapy. Frequently it may be necessary to administer the physical therapy in an intensive, inpatient program, both to break the pain-disability cycle and to remove the patient from a stressful family environment that may have initiated or prolonged the syndrome. The use of steroids (dexamethasone) had no appreciable effect on the clinical course in these children.

Cortical-Evoked Potentials and Saliva Levels as Basis for the Comparison of Pure Analgesics to Analgesic Combinations

Cortical-evoked potentials, pain ratings and thresholds of sensation were monitored after tooth pulp stimulation under the influence of marketed mixtures of analgesics. Simultaneously the saliva levels of the individual pharmacological active components of these mixtures were measured by high-performance thin-layer chromatography. The action of the mild analgesics in the mixtures was calculated from the linear correlations of changes in cortical-evoked potential with saliva levels of the analgesics. The ineffectiveness of low doses of salicylamide in the combinations was demonstrated by this method. None of the investigated combination products was superior to the same doses of either acetylsalicylic acid, paracetamol or phenazone.

Avascular necrosis of bone complicating treatment of malignant lymphoma

Over a 15-year period, 12 patients were seen at the Ontario Cancer Institute in whom avascular necrosis of bone developed after or during treatment for malignant lymphoma. All but one were treated with systemic chemotherapy that included high-dose intermittent corticosteroids. The average time to onset of symptoms was 34 months (range, eight to 72 months) after an average of 9.0 g of prednisone (range, 1.4 to 18.75 g). The one exception was a patient with Hodgkin's disease treated by pelvic radiation alone who had development of avascular necrosis of the femoral head within one month of irradiation. More than one joint was involved in 58 percent of patients. Six patients required surgery (usually hip replacement) but two patients had no evidence of deterioration over many years (average, seven years) and three patients had minimal symptoms easily controlled by mild analgesics up to six years after diagnosis. The evidence implicating corticosteroids in the development of avascular necrosis is presented and the various hypotheses of pathogenesis are reviewed, The predominance of Hodgkin's disease over non-Hodgkin's lymphomas (5:1) in this and other series and the identification of one patient with Hodgkin's disease with development of avascular necrosis within one month of radiotherapy treatment suggests that Hodgkin's disease itself may predispose to this condition.

Costochondritis in adolescents

One hundred adolescent clinic patients who complained of chest or upper abdominal pain were evaluated. Seventy-nine were found to have only tender costal cartilages. Costochondritis pain originates in the anterior chest wall and may radiate into the chest, back, or abdomen. It is reproducible by palpating the affected costal cartilage. Costochondritis was more often unilateral than bilateral (P = 0.001), and in unilaterally affected patients (P less than 0.005), is involved the left side more than the right. The left fourth sternocostal cartilage was involved most frequently. A simple program of mild analgesics and reassurances was sufficient treatment in all cases. These findings suggest that chest pain and upper abdominal pain in adolescents rarely arise from serious problems. Adolescents are normally hypersensitive about physical symptoms, but they can be effectively reassured and an expensive diagnostic and treatment program can be avoided.

Georgetown University Symposium on Analgesics

The principal over-the-counter mild analgesics possess antipyretic/anti-inflammatory properties (the salicylates) and antipyretic properties (acetaminophen). These drugs have long been available, are widely used throughout the world, and in general are well tolerated. Despite long-term global experience with both drugs (the salicylates were introduced 80 years ago, and acetaminophen has been in clinical use since 1893), only in the last decade have many of the fundamental pharmacologic properties of both drugs yielded to investigation. This special issue of theArchives of Internal Medicineis devoted to a comprehensive and up-to-date review of the clinical properties, similarities, and dissimilarities of these two compounds. It came about as a result of a lively conference held in Washington, DC, between internationally preeminent scientists and clinical investigators, with an audience consisting of clinicians, scientists, and allied health professionals. We open with Dr Ramwell's review of the known mechanisms of action of both drugs, the concepts

Quantifizierung der Dämpfung in der Schmerzempfindung mit Hilfe evozierter Potentiale nach Gabe schwacher Analgetika

Evoked potentials resulting from stimulation of tooth pulp with rectangular impulses were chosen for the indication of the analgesic activity of mild analgesics. If the stimuli were perceived subjectively as equally painful, the amplitudes of the evoked potentials were intraindividually well reproducible. The results are reproducible within one day as well as on different days. According to the large interindividual variation in the amplitude of the evoked potentials, the percentual reduction of the amplitude was a better measure for the analgesic action than the absolute height of the signal. Interindividually, the latencies have shown clear differences whereas they were reproducible for the individuum. The curves for: 1. The percentual reduction of the evoked potentials 2. The diminuation of the subjective pain response 3. The increase in the sensitivity threshold after the application of the drug were principally similar. The results indicate, that the evoked potentials may represent a more sensitive measure of experimentally induced pain in subjective methods.

Mild analgesics in postoperative pain.

1 The intensity of postoperative pain is influenced by many factors, for example, individual variation, site of incision and type of operation, anaesthetic technique, and the interval from the end of operation to the appearance of pain. 2 These factors affect the efficacy of analgesics. 3 Mild analgesics provide adequate pain relief in half of our patients in the immediate postoperative phase when the pain is slight to moderate. 4 The maximum effect of mild analgesics corresponds to that produced by morphine 6-10 mg. Adequate analgesia may not therefore be provided for the treatment of severe postoperative pain unless narcotic analgesics have been used peroperatively. 5 When mild analgesics are combined with narcotics synergism is achieved. 6 As postoperative pain decreases with time, mild analgesics usually provide adequate pain relief on the first and following postoperative days.

Mild analgesics--a re-evaluation, Geneva, October 1979.

British Journal of Clinical PharmacologyVolume 10, Issue S2 p. 215S-411S Free Access Mild analgesics-a re-evaluation, Geneva, October 1979. JV Jones, JV JonesSearch for more papers by this authorJM Steiner, JM SteinerSearch for more papers by this author JV Jones, JV JonesSearch for more papers by this authorJM Steiner, JM SteinerSearch for more papers by this author First published: April 1980 https://doi.org/10.1111/j.1365-2125.1980.tb01803.xCitations: 21AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume10, IssueS2April 1980Pages 215S-411S ReferencesRelatedInformation

Clinical evaluation of mild analgesics.

1 Mild analgesics pose particular problems in evaluation because of difficulty in getting suitable patients, the frequent use of oral administration and their long-term use. 2 Despite their limitations it is possible to quantify both pain severity and pain relief using either 'pain scores' or 'visual analogues'. 3 A trained observer can add information in addition to the patient's interpretation of pain. 4 There are particular problems using crossover studies with analgesics and the sequential method of evaluating results is not as useful with mild analgesics as with more potent drugs. 5 Opinions differ as to the importance of dummy medication in the study of analgesic drugs; difficulties may arise from ethical as well as practical reasons. 6 In the overall evaluation of mild analgesics it is important to consider their long term side effects. 7 Access to a large number of patients with a constant pain of 6-8 h duration and a smaller number with long-term pain is the most important prerequisite in the evaluation of mild analgesic drugs.

Biodistribution of mild analgesics.

1 Macro-autoradiographic methods were used to assess the biodistribution of [3H]-, or [14C]-acidic (aspirin, indomethacin, phenylbutazone) and non-acidic (antipyrine, aminopyrine, paracetamol) mild analgesics in rats with carrageenan-induced inflammation. 2 At anti-inflammatory doses all the acidic drugs (and/or their metabolites) were found to reach high concentrations in the stomach wall, liver, blood and bone marrow, kidney cortex and the inflamed tissue, that is, the tissues in which these drugs exert their therapeutic or side-effects. 3 In contrast, at analgesic doses, the non-acidic mild analgesics (and/or their metabolites) are equally distributed throughout the body with the exception of the gastro-intestinal lumen and the liver. This distribution pattern correlates well with the lack of acute side-effects and anti-inflammatory action of these drugs at therapeutic doses.

Hepatotoxicity of mild analgesics.

1 Hepatotoxicity is rare when mild analgesics are used in normal therapeutic doses. 2 The potential of aspirin and salicylates to cause hepatotoxicity has been only recently recognized. 3 Salicylate hepatitis is often asymptomatic, and may only be revealed by finding elevated levels of aminotransferases. 4 Most cases have occurred in children or young adults with connective tissue diseases, who take high doses of salicylates for long periods. 5 Hepatic injury is not recognized as a complication of acute aspirin poisoning. 6 Following overdosage of paracetamol, a toxic intermediate metabolite causes acute hepatic necrosis which may be fatal. 7 Cysteamine, methionine and N-acetylcysteine confer protection against this severe liver damage, but the time between overdosage and treatment is critical. 8 The chronic therapeutic use of paracetamol should be considered a potential but very rare cause of active chronic hepatitis. 9 There is no clear evidence of phenacetin hepatotoxicity in man. 10 Phenylbutazone may cause liver injury and other analgesics can cause hypersensitivity reactions in which the liver is involved.

Acute intoxication and illness due to mild analgesics.

1 Acute intoxication with mild analgesics is relatively uncommon in France. In fact, these drugs have accounted for only about 3.5% of acute drug intoxications seen at the Fernand Widal Hospital, Paris, over the past 10 years. 2 On the other hand, 23% of adverse reactions recorded by a drug monitoring service have been attributed to mild analgesics. 3 It is very difficult to establish the true incidence of acute toxicity and adverse reactions caused by these drugs. They are usually taken without medical supervision; it is often difficult to ascribe toxicity to a single agent when combination products are taken so frequently; and the underlying illness and the use of other drugs must also be considered. 4 The methods currently used to obtain adverse reaction and toxicity data have many disadvantages and shortcomings.

Arachidonic acid metabolism, pain and hyperalgesia: the mode of action of non-steroid mild analgesics.

1 Cyclo-oxygenase products such as prostaglandins of the E series and prostacyclin produce the hyperalgesia associated with inflammation. 2 These substances may cause pain and incapacity in some inflammatory conditions. 3 Prostaglandin E2 sensitizes the chemical receptors of afferent pain endings to other inflammatory mediators such as bradykinin and histamine. 4 Unstable intermediates formed in the generation of prostaglandins may also play a role in the production of pain. 5 Drugs such as indomethacin and aspirin which are potent inhibitors of prostaglandin biosynthesis may exert their analgesic effect through this mechanism.

Epidemiological evaluation of rare side-effects of mild analgesics.

1 Major adverse reactions to mild analgesics, unless these drugs are abused or taken in high doses, are believed to be rare. 2 However, because of the massive and universal use of these drugs, quantitative measurement of the risk involved is imperative. At present, contradictory regulatory decisions about the use of mild analgesics are based on circumstantial evidence. 3 It is only by the conduct of epidemiological studies that data leading to decisions based on scientifically sound judgments may be obtained.

Clinical evaluation of mild analgesics in post partum pain.

1 The design of a clinical study evaluating mild analgesics in post partum patients is dependent on the purpose of the study. Work intended to determine whether a compound has any analgesic properties, requires a different design from a study positioning a drug in the continuum of available oral analgesics. A vital aspect of a well designed study is randomization of the treatments. The level of initial pain and the type of pain must also be stratified. The use of a cross-over design can decrease patient variation and is therefore very valuable. However, order effects need to be measured. 2 The parameters obtained from the data extend beyond the directly elicited to statistically derived variables. We have derived a method to assign mathematically a numerical score to each patient's verbal report. 3 To reach a meaningful conclusion, one should base the evaluation of the compound on several studies. The interpretation of data from one study must be made with great caution, because of individual variation. In the magnitude of the response some experimenters have found differences between uterine cramp and episiotomy pain, but these have not been consistently reproduced by others.

Nephrotoxicity of mild analgesics in the Gunn strain of rat.

1 Homozygous members of the Gunn strain of rat, mutant Wistars jaundiced from lack of the enzyme uridine diphosphate glucuronyl transferase, are highly susceptible to analgesic-induced renal papillary necrosis. 2 A single oral dose of aspirin, phenacetin or paracetamol will produce the lesion, a circumstance which does not occur in other strains. 3 The reasons for this susceptibility have not been determined, but the experimental model should prove useful in further studies of the nephrotoxicity of analgesic drugs.