Weak Analgesics Research Articles

THE MANAGEMENT OF METASTATIC BONE PAIN IN A DEVELOPING COUNTRY: THE ROLE OF RADIOTHERAPY AS AN ADJUNCT TO WEAK OPIOIDS

SUMMARYBone pain secondary to metastatic cancer is the commonest intractable pain and is a major concern in most oncology units the world over. Cancer pain management is multidisciplinary in approach, so there is no universal or singular modality of treatment. In a developing country like Nigeria, only external radiotherapy and adjuvant weak opioids are readily available, so it is of interest to review the response of these patients to this management option. This is a retrospective review of 92 patients aged 16–80 years with radiologically confirmed metastatic bone disease associated with pain who received external radiotherapy and weak analgesics. The results showed that 23 (25%) patients had a complete response and 67 (73%) had a partial response within four weeks of treatment. Total response was over 90%, which suggests external radiotherapy has an effective palliative role. The study also demonstrated the pattern of bony involvement among the common cancers seen in our environment. The availability of strong opioids (e.g. morphine and pethidine) will obviously consolidate the gains achieved with external radiotherapy in the management of metastatic bone pain in our environment.

Pregnancy outcome after suicide attempt by drug use: a Danish population-based study

Background. It is important to study the side-effects of drugs taken during pregnancy, however the findings are difficult to interpret because of a low exposure level, uncertainty of actual drug consumption and confounding by indication. Experience from accidental or intended drug intoxications may bypass some of these methodological shortcomings. Our aim was to examine reproductive failures and child health following a single drug overdose taken prior to or during pregnancy. Methods. Women diagnosed with a drug intoxication during pregnancy were identified in the Regional Hospital Discharge Registry of North, Jutland from 1977 to 1999 by linkage of diagnoses for abortion and delivery with diagnoses for intoxication. Hospital medical records were reviewed to obtain data on drug use, dosage, and pregnancy outcome (legally induced abortion/miscarriages/data on birth outcome). The hospitalization history of the children was followed for a mean of 9 years with a maximum of 20 years. Results. Of 122 women studied, 44 wanted an elective abortion, 17 experienced miscarriage, and 61, exposed mainly to weak analgesics and psychotropic drugs, gave birth to 62 infants. We estimated the proportion of miscarriage to be almost doubled, whereas there was no increased risk of congenital abnormalities or prematurity in women exposed to a drug overdose compared with the background population. Conclusions. A drug overdose shortly before or during pregnancy seems to be associated with a substantially increased risk of miscarriage, but there was no increase in fetal pathology at birth among fetuses surviving till birth.

Randomized Trial of Opioids Versus Tricyclic Antidepressants for Radiation-Induced Mucositis Pain in Head and Neck Cancer

Patients who receive radiotherapy for head and neck cancer are likely to develop painful mucositis. The pain is characterized by a burning or stinging sensation similar to neuropathic pain sensations. The purpose of the present study was to compare the analgesic effect of a tricyclic antidepressant (TC), commonly used in the treatment of neuropathic pain, with the effect of opioids on radiation-induced mucositis pain. Forty-three patients receiving 66–68 Gy external radiation according to the DAHANCA guidelines (the Danish Head and Neck Cancer Study Group) were randomized to either morphine or TC when mucositis pain was insufficiently managed with weak analgesics. Patients with insufficient pain control in either treatment arm received supplementary medication from the opposite treatment arm. Pain was evaluated weekly using a VAS scale and the McGill Pain Questionnaire. The degree of mucositis and the degree of depression were measured at the same time intervals. Twenty-two patients entered the opioid arm and 21 the TC arm. Two patients in each arm were non-evaluable. VAS pain scores were significantly reduced in the opioid treatment arm one week after randomization (p=0.01). Eight patients in the TC arm were managed with TC alone, but for 11 patients it was necessary to add morphine. The 20 evaluable patients in the morphine arm required no additional treatment. There were no significant differences in side effects between the two groups. Higher pain scores in the TC arm, but not in the opioid arm, were significantly correlated with higher BDI scores. Some head and neck cancer patients with radiation-induced nucositis pain may have sufficient pain control on TC alone. This might be useful in patients with relative counter-indications to opioid treatment.

Clinical and descriptive analysis of chronic daily headaches

With an ad hoc, previously validated clinical record, we analysed the headache characteristics in 245 patients (F, 78.4%, M, 21,6%; mean age, 43.1±12.9 years) affected by chronic daily headache (CDH) attending 9 Italian headache centers. Migraine without aura was the episodic headache preceding CDH in 72.3% of the cases. We divided CDH into 3 categories: chronic tension-type headache (CTTH), chronic coexisting migraine and tension-type headache (CCMTTH), and chronic migraine (CM). CCMTTH accounted for 46.5% of the cases, followed by CM (30.2%) and CTTH (23.3%). Female prevalence was more marked in CCMTTH and CM groups, in which episodic headache started earlier. Migraine without aura was the episodic headache preceding CDH not only in most cases of CCMTTH (83.0%) and CM (91.9%), but also in 25% of CTTH patients.Analgesics misuse (abuse of weak analgesics and/or combination drugs in almost all the cases) prevailed among CCMTTH (61%) and CM (89%) patients with respect to CTTH patients (37%).

Risk factors for renal cell carcinoma in Denmark: role of medication and medical history.

Several recent studies of risk factors for renal cell carcinoma have indicated that use of diuretics may increase risk of this cancer. It has also been suggested that use of weak analgesics, which are known to increase risk of cancer of the renal pelvis and ureter, may also be associated with an increased risk of renal cell carcinoma--the most frequent type of kidney cancer. A population-based case-control study was undertaken to investigate the role of diuretics, other anti-hypertensive drugs, analgesics, and medical history in the aetiology of renal cell carcinoma. The study base was the total Danish population, and 368 histologically verified cases and 396 sex- and age-matched controls who were interviewed from February 1989 to May 1992. Response rates were 76% among cases and 79% among controls. We found no general increase in risk among users of diuretics or analgesics, although women taking loop diuretics and heavy users of acetyl salicylic acid had slightly increased risks. The use of nondiuretic anti-hypertensive medications was associated with decreased risk in women. We found non-significantly increased risks for history of hypertension and other cardiovascular disorders. We also observed elevated risks for urological disorders in both sexes which may be a result of recall bias. This study provides only limited support for the suggested association between risk of renal cell carcinoma and use of diuretics and analgesics. The coexistence of renal cell carcinoma and cardiovascular diseases could be caused by risk factors that are common to these conditions.

Dose-ranging study of oxycodone for chronic pain in advanced cancer.

We assessed the analgesic efficacy and safety of single-entity oxycodone solution at doses greater than 10 mg orally every 4 hours in 24 patients with chronic cancer pain not controlled by weaker analgesics. Twenty of 24 patients completed the study. Pain relief was obtained with doses up to 60 mg every 4 hours. When oxycodone was taken for long periods, further dose increments could be made safely. The side effects of oxycodone are mild, and common to all opioids, with sedation and constipation most frequent. Nausea was more common in females in all age groups and in patients of either sex less than 50 years of age. Episodes of serious toxicity were rare, and responded to dose reduction. Patients older than 65 years required lower doses, suggesting pharmacokinetic similarities between oxycodone and morphine. Patients changed from oral oxycodone to morphine remained pain-free when relative milligram potency ratios of 1:1 to oral morphine and 3:1 to intravenous morphine were used. Oxycodone has been shown for the first time to be as versatile and flexible as oral morphine in the management of chronic pain in patients with advanced cancer.

Opioid Agonist-Antagonist Drugs in Acute and Chronic Pain States

The agonist-antagonist opioid analgesics are a heterogeneous group of drugs with moderate to strong analgesic activity comparable to that of the pure agonist opioids such as codeine and morphine but with a limited effective dose range. The group includes drugs which act as an agonist or partial agonist at one receptor and an antagonist at another (pentazocine, butorphanol, nalbuphine, dezocine) and drugs acting as a partial agonist at a single receptor (buprenorphine). These drugs can be classified as nalorphine-like or morphine-like. Meptazinol does not fit into either classification and occupies a separate category. Pentazocine, butorphanol and nalbuphine are weak mu-antagonists and kappa-partial-agonists. All three drugs are strong analgesics when given by injection: pentazocine is one-sixth to one-third as potent as morphine, nalbuphine is slightly less potent than morphine, and butorphanol is 3.5 to 7 times as potent. The duration of analgesia is similar to that of morphine (3 to 4 hours). Oral pentazocine is closer in analgesic efficacy to aspirin and paracetamol (acetaminophen) than the weak opioid analgesics such as codeine. Neither nalbuphine nor butorphanol is available as an oral formulation. At usual therapeutic doses nalbuphine and butorphanol have respiratory depressant effects equivalent to that of morphine (though the duration of such effects with butorphanol may be longer). Unlike morphine there appears to be a ceiling to both the respiratory depression and the analgesic action. All of these 3 drugs have a lower abuse potential than the pure agonist opioid analgesics such as morphine. However, all have been subject to abuse and misuse, and pentazocine (but not the others) is subject to Controlled Drug restrictions. Buprenorphine is a potent partial agonist at the mu-receptor, and by intramuscular injection is 30 times as potent as morphine. A ceiling to the analgesic effect of buprenorphine has been demonstrated in animals and it is also claimed in humans. However, there are no reliable data available to define the maximal dose of buprenorphine in humans. A practical ceiling exists for sublingual use in that the only available formulation is a 2 micrograms tablet and few patients will accept more than 3 or 4 of these in a single dose. The duration of analgesia is longer than that of morphine, at 6 to 9 hours. There have been suggestions that buprenorphine causes less respiratory depression than morphine, but viewed overall it appears that in equianalgesic doses the 2 drugs have similar respiratory depressant effects.(ABSTRACT TRUNCATED AT 400 WORDS)

Modified formalin test: characteristic biphasic pain response

A modified formalin test in mice was investigated. The pain response curve induced by 0.5% formalin was biphasic, having 2 peaks, from 0 to 5 min (first phase) and from 15 to 20 min (second phase). A low concentration of formalin was used, allowing the effects of weak analgesics to be detected. Centrally acting drugs such as narcotics inhibited both phases equally. Peripherally acting drugs such as aspirin, oxyphenbutazone, hydrocortisone and dexamethasone only inhibited the second phase. Aminopyrine and mefenamic acid which acted on both central and peripheral sites inhibited both phases, but the second phase was inhibited by lower doses. Thus, this method enables one to easily distinguish the site of action of analgesics. Furthermore, pain response in the first phase was inhibited by capsaicin-treated desensitization and Des-Arg 9-(Leu 8)-bradykinin (bradykinin inhibitor). The second phase was inhibited by compound 48 80 pretreatment, indomethacin and bradykinin inhibitor. Therefore, it is suggested that substance P and bradykinin participate in the manifestation of the first phase response, and histamine, serotonin, prostaglandin and bradykinin are involved in the second phase. These results indicate that the first and second phase responses induced by formalin have distinct characteristic properties, and it is a very useful method for examining pain, nociception and its modulation by pharmacological or other means.

New 4-(heteroanilido)piperidines, structurally related to the pure opioidagonist fentanyl, with agonist and/or antagonist properties

A research program based on certain heterocyclic modifications (12-50) of the fentanyl (1) molecule has generated a novel class of opioids. In the mouse hot-plate test, these compounds were weaker analgesics than 1. Two types of antagonists were observed in morphine-treated rabbits: those (e.g., 28) that reversed both respiratory depression and analgesia and those (e.g. 32) that selectively reversed respiratory depression. Evaluation of in vitro binding affinities to rat brain opioid receptors was inconclusive for a common locus of action for the agonist as well as the antagonist component. Further pharmacological evaluation of 32, N-(2-pyrazinyl)-N-(1-phenethyl-4-piperidinyl)-2-furamide, in the rat showed it to be a potent analgesic (ED50 = 0.07 mg/kg, tail-flick test) with little cardiovascular and respiratory depression when compared to fentanyl.

In-vitro transdermal permeation of oxycodone: (I) effect of PH, delipidization and skin stripping

AbstractThe effect of pH, skin stripping and delipidization on the in-vitro transdermal permeation of a weak base analgesic, oxycodone (pKa=8.53), was studied using hydrodynamically calibrated Valia-Chien diffusion cells. Saturated oxycodone. HCl solutions in citrate-phosphate buffers ranging from pH 4 to 10 were used as the donor solution. Skin samples from the abdominal and dorsal sites of hairless rats, abdominal site of hairless mouse, rabbit pinna ear, as well as human cadaver skin were used in permeation studies. The pHs at which maximum flux attained varied from 6.5 to 7.5 depending upon animal model. The permeabilities of protonated form through intact skin of all the animal models used, was about 7-15 fold lower than that of nonionic form. The unexpected high permeation rate at pHs ranges 4 to 6.5 across human cadaver could be attributed to the possible damage upon storage. The skin stripping and delipidizaton process appeared to increase the permeation rates of oxycodone and the degree enhanceme...

The clinical usefulness of agonist-antagonistic opioid analgesics in chronic pain

The mixed agonist-antagonist analgesics do not have a major role in the treatment of chronic pain. Pentazocine, the first and most widely used of this group of drugs has two major limitations: by mouth it is not a strong analgesic, but is closer in efficacy to the peripherally acting drugs aspirin and paracetamol than the weak opioids; and its use is associated with psychotomimetic side effects in 10–20 percent of patients. The weak opioid analgesics codeine and dextropropoxyphene are more effective and better tolerated than pentazocine. Buprenorphine is the most useful of the agonist-antagonists in chronic pain patients. It is potent, long-acting (6–9 h) and effective when given sublingually. However, it has a limited effective dose range and produces the same side effects as morphine-like drugs, possibly more frequently at equianalgesic doses. It may be used in the treatment of cancer pain, or in patients with chronic arthritides or other forms of chronic non-cancer pain who require a potent conventional analgesic, as an alternative to the weak opioids or to morphine in low doses. Nalbuphine and butorphanol are only available for parenteral administration which means that their usefulness in the treatment of chronic pain is limited. Meptazinol is restricted by its manufacturers to ‘short term’ treatment and there is little information on its use in chronic pain patients.

Analgesic sensitivity of two post-partum pain models

Post-partum uterine cramping and episiotomy pain are established, frequently used, clinical pain models for efficacy trials of investigational new analgesic agents. To determine the respective assay sensitivity of these two models in assessing relative efficacy, we reviewed data from 6 phase II, randomized, stratified, parallel, placebo-controlled, double-blind, single-dose studies involving hospitalized women with moderate or severe post-partum uterine cramping (332 patients) or episiotomy pain (434 patients). Using subjective reports as indices of response, patients rated pain intensity and relief at periodic interviews for 6–7 h. Post-partum uterine cramping showed excellent assay sensitivity for detecting differences among peripherally acting analgesics. In the same clinical trial this model could discriminate between a new drug and aspirin 650 mg, a standard reference analgesic, and between 2 graded doses of the new active agent (i.e., good upside sensitivity). In addition the uterine cramp model showed separation between placebo and all active agents (i.e., good downside sensitivity). Episiotomy pain demonstrated similar upside and downside discrimination in clinical trials of several weak centrally acting drugs. These data suggest that post-partum cramping is an excellent pain model for analgesic investigation of new non-steroidal anti-inflammatory drugs, and episiotomy pain for new weak narcotic and opioid analgesics.

Drug abuse in migraine patients

Records of all patients discharged with a diagnosis of migraine from 2 Danish neurological departments were examined to determine the incidence of drug abuse. These departments had fixed uptake areas with a population of approximately 500,000 during the 5 year study period (1-1-1976-31-12-1980). Patients were selected for detailed analysis if (1) they used morphinomimetic drugs once a month or more, (2) took 7 or more tablets of weak analgesics a day or (3) consumed more than 60 mg ergotamine a month. A total of 92 patients fulfilled these criteria, 27 only because of ergotamine overuse. Injections of morphinomimetic drugs were given once a week or more frequently to 32 patients. These patients also usually had an escalating consumption and were usually regarded as abusers by their doctors. During admission morphinomimetics were discontinued. None deteriorated, 1 3 remained unchanged whereas 2 3 improved. Thus 32 patients can be regarded as abusers of morphinomimetics which represents an annual incidence of 13 per million inhabitants. We caution against the use of morphinomimetics in migraine.

Abuse of weak opioid analgesics.

Abuse of weak opioid analgesics.

A modified formalin test for measuring analgesia in mice.

A simple method for assessing pain and analgesia in mice was developed by modification of the formalin test. Formalin was injected into the forepaw of a mouse and the durations (in sec) spent in licking and biting responses were measured. These behavioral responses being very distinct, pain assessment was easily performed without the experimenter's subjective assessment. The use of the duration of pain during each 5 min block of 2 peak points enables determination of the analgesic effect quantitatively and shortening of the experimental time. As a low concentration of formalin (0.5%) was used in this method, the analgesia of weak nonnarcotic analgesics was detectable as well as that of narcotic ones and tissue damage was not elicited. Furthermore, this method enables to distinguish roughly the action site of analgesics between the central and peripheral one.

Antipyrine - new light on an old drug.

The time courses of analgesic activity of 4 different tablets containing different amounts of antipyrine were determined in 14 volunteers using electrical tooth pulp stimulation to elicit pain. Drug action was monitored by following somatosensory evoked potentials obtained from electroencephalographic measurements as well as pain rating and pain threshold determination. The results were compared with data obtained after administration of 1000 mg acetaminophen and two different doses of aspirin (500 and 1000 mg). At the same time drug concentration in saliva of the same volunteers was analyzed by quantitative in situ thin-layer-chromatography to investigate the pharmacokinetics. Furthermore, the in vitro drug release from the different tablets was studied with a continuous flow cell model. Antipyrine produced reliable analgesic activity. The onset of action was significantly faster than after administration of the same dose of aspirin, and the effect lasted longer than after intake of the same dose of acetaminophen. Comparison of the drug action and drug level in the body showed an excellent correlation between pharmacodynamics and pharmacokinetics. The study confirms our earlier findings on the value of somatosensory evoked potentials as a method to investigate the pharmacodynamics of weak analgesics in humans. The results also suggest to reconsider the use of antipyrine as an over-the-counter analgesic.

Morphine-induced analgesia and explosive motor behavior in an amphibian

Morphine sulfate is a weak analgesic in the frog Rana pipiens pipiens, causing a slight increase in nociceptive threshold at a dose of 10 mg/kg and a pronounced increase at 100 mg/kg. Morphine-induced analgesiapersists for at least 165 min and is significantly attenuated by naloxone. The analgesic doses of morphine are well below the lethal dose and are without noticeable effect on the behavior of the frogs or their responses to non-painful stimuli. Higher doses of morphine (320 and 640 mg/kg) induced a state of hyper-responsiveness to sensory stimuli similar to the explosive motor behavior induced in rats by microinjection of morphine into the periaqueductal gray.

Changes in cortical evoked potentials as correlates of the efficacy of weak analgesics

The relationship between subjective measurements of pain (pain report and threshold of sensation) and evoked potentials following painful electrical stimulation of tooth pulp was evaluated after intake of different weak analgesics. These time-response curves for the dolorimetric parameters were correlated to the in vivo drug levels obtained in corresponding experiments by analyzing saliva. Based on the comparison between the drug levels of analgesics in saliva on the one hand and the threshold of sensation, the pain rating and changes in the amplitude of the cortical EP on the other hand, the sensitivity of the EP to changes in drug concentration was superior than to subjective pain judgement. The data were correlated to clinical pain relief investigations. The results support the suggestion of earlier research that EP evaluation may well serve as a correlate for laboratory pain.

Rapid thin-layer chromatography of various weak analgesics in saliva

A thin-layer chromatographic method was developed to analyze phenacetin, 4-amino-phenazone and N-methyl-4-aminophenazone (5 and 1.25 μg/ml); bucetin (4-ethoxy-β-hydroxybutyranilide), propyphenazone and N-acetyl-4-aminophenazone (2.5 and 1.25 μg/ml); phenazone (15 and 1.25 μg/ml); and N-acetylsalicylamide (0.25 μg/ml). The method was designed to study the bioavailability of different commercial tablets from salivary concentration data.

HPLC-determination of some antiinflammatory, weak analgesic and uricosuric drugs in human blood plasma and its application to pharmacokinetics.

HPLC-determination of naproxen, indomethacin, ketoprofen, fenoprofen ibuprofen, diclofenac sodium, tolfenamic acid, phenylbutazone, mofebutazone, salicylic acid, acetylsalicylic acid, phenacetin, paracetamol, sulfinpyrazone and probenecid by means of an adjustable, rapid accurate and specific method is described. Plasma samples of 0.2 ml were deproteinised and the drugs extracted simultaneously with pure acetonitrile. Aliquots of 25 mul of this primary extract were directly injected on the column. As elution solvent for drug screening was basically used 55% methanol in 50 mM phosphate buffer at pH 4.0. Optimal separation of some drugs or reasonable elution times for others were obtained by varying the methanol concentration of the elution solvent or possibly its pH. The method used for individual drug determinations is very applicable for therapeutic monitoring purposes as well as for use in pharmacokinetic investigations. As an example, the practical detection limit for naproxen in plasma was about 0.2 microgram ml-1. By concentrating the extract this could be lowered to about 0.04 microgram ml-1. The method was applied in a study of the pharmacokinetics of naproxen in a person, who ingested a single oral dose of 2.5 mg kg-1. Pronounced two-compartment kinetics were found. Vc was 0.038 1 kg-1, Vdss 0.138 1 kg-1, t 1/2 (beta) 21.3 hrs, t 1/2 (alpha) 0.99 hr and t 1/2 (ka) 0.67 hr.