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PubMed2006

Fracture risk associated with the use of morphine and opiates.

OBJECTIVES: To study the effect of morphine and opiates on fracture risk. DESIGN: Case-control study. SETTING: Nationwide register-based study. SUBJECTS: Cases were all subjects with any fracture sustained during the year 2000 (n = 124,655). For each case, three controls (n = 373,962) matched on age and gender were randomly drawn from the background population. The primary exposure variables were use of morphine and opiates. Morphine and other opiates had been used by 10 015 (8.0%) of the case subjects and 12 108 (3.2%) of the controls. Adjustments were made for several confounders including prior fracture, and use of weak analgesics [nonsteroidal anti-inflammatory drugs, acetylsalicylic acid (ASA) and acetaminophene]. The effect of dose was examined by stratifying for cumulated dose (defined daily dose). MAIN OUTCOME MEASURE: Fracture. RESULTS: Morphine (1.47, 95% CI 1.37-1.58), fentanyl (2.23, 95% CI 1.89-2.64), methadone (1.39, 95% CI 1.05-1.83), oxycodone (1.36, 95% CI 1.08-1.69), nicomorphine (1.57, 95% CI 1.38-1.78), ketobemidone (1.07, 95% CI 1.02-1.13), tramadol (1.54, 95% CI 1.49-1.58) and codeine (1.16, 95% CI 1.12-1.20) were all associated with an increase in overall fracture risk. No increase was present for buprenorphine (0.86, 95% CI 0.79-0.95), pethidine (0.98, 95% CI 0.89-1.08), dextropropoxiphene (1.02, 95% CI 0.90-1.16), and combinations of ASA and codeine (0.94, 95% CI 0.88-1.01). CONCLUSIONS: An increased fracture risk is seen in users of morphine and opiates. The reason for this may be related to the risk of falls due to central nervous system effects such as dizziness.

Accidental Falls↗
PubMed2003

Evaluation of intravenous fluorescein in intradermal allergy testing in psittacines.

This study was designed to improve the clinical feasibility of intradermal skin testing of psittacine birds using intravenous fluorescein stain. Twenty-five healthy, anaesthetized Hispaniolan Amazon parrots (Amazona ventralis) were injected intravenously with 10 mg kg-1 fluorescein-sodium 1% followed by intradermal injections of 0.02 mL phosphate-buffered saline, histamine phosphate (1:100,000 w/v) and codeine phosphate (1:100,000 w/v) at the sternal apteria. Wheal diameters of reaction sites were measured grossly and under illumination with a Wood's lamp after 5 and 10 min. Fluorescence-enhanced injection sites were scored between 0 and 2, with 0 equivalent to normal skin and 2 equivalent to a plucked feather follicle. The presence of a fluorescent halo around intradermal injections was also recorded. Under Wood's light illumination at 10 min, histamine and saline were evaluated as positive and negative controls, respectively, based on a positive test having a halo and a score of 2. Sensitivity and specificity were each 76% for halo, 84 and 42% for score and 64 and 77% for combination of score and halo, respectively. Further, mean histamine reactions were significantly larger than codeine phosphate and saline (8.8 +/- 0.4 mm; 7.2 +/- 0.3 mm; 5.9 +/- 0.6 mm); however, this finding was not consistent in individual birds. Wheal size, halo presence and score were affected by site location independent from the injected compound. Intravenous fluorescein improved the readability of avian skin tests; however, the compounds tested raised inconsistent reactions in wheal size, score or halo presence. The compound-independent site effect raises concern on the validity of avian skin testing and warrants investigation of other techniques such as in vitro allergy testing. Based on our findings, intradermal allergy testing in psittacines with or without fluorescein is unreliable and cannot be recommended for practical clinical use.

Animals↗
PubMed2006

Etoricoxib pre-medication combined with intra-operative subacromial block for pain after arthroscopic acromioplasty.

BACKGROUND: Arthroscopic shoulder surgery under general anaesthesia is often associated with severe post-operative pain which may delay discharge and the start of rehabilitation. Etoricoxib is a new cyclo-oxygenase-2 inhibitor with a long duration of action and a lack of a deteriorating effect on platelet function. Therefore, the effect of pre-operative etoricoxib combined with local anaesthesia on post-operative pain and the discharge profile was studied in day-surgery patients undergoing arthroscopic shoulder surgery under general anaesthesia. METHODS: Thirty ASA I-II adult patients scheduled for arthroscopic shoulder surgery were enrolled in this randomized prospective study. Half of the patients received etoricoxib 120 mg orally (group E) and the other half received placebo tablet orally (group C) 1 h before surgery. All patients received 20 ml of bupivacaine 2.5 mg/ml solution with epinephrine at the start of surgery and 20 ml of bupivacaine 5.0 mg/ml solution with epinephrine at the end of surgery into the subacromial space. All patients received general anaesthesia with spontaneous breathing via a laryngeal mask. In the post-anaesthesia care unit, pain was assessed on a scale from 0 to 10 (visual analogue scale, VAS) and intravenous fentanyl 25 microg was administered as scheduled (VAS > or = 3). In the day-surgery unit and at home, the analgesic was a tablet containing paracetamol 500 mg + codeine 30 mg (VAS > or = 3), as needed. RESULTS: Patients in group E reported lower post-operative pain scores at 30, 60, 120 (P < 0.01) and 180 min (P < 0.05) after surgery, and longer time to first analgesic use (P < 0.05). Patients in group E required less fentanyl (P < 0.05) and were discharged more quickly (P < 0.05) than patients in group C. Patients in group E had a lower cumulative consumption of paracetamol + codeine tablets (P < 0.05) and lower pain scores (P < 0.05) during 7 days at home than patients in group C. Adverse events were rare in both groups. CONCLUSION: In patients having arthroscopic shoulder surgery under general anaesthesia combined with intra-operative subacromial regional analgesia, etoricoxib 120 mg reduced immediate and late post-operative pain, and facilitated early post-operative discharge.

Adult↗
PubMed1981

the consultant pharmacist and analgesic/anti-inflammatory drug usage in a geriatric long-term facility.

The contribution of a consultant pharmacist to a 33-month study of analgesic and anti-inflammatory drug usage by 210 elderly long-term patients was evaluated by a fifth-year pharmacy student. In the 143 patients who used analgesics and anti-inflammatory agents, significant changes were noted, viz, decreased use of codeine (p = .002); increased use of acetaminophen (p = .003) and anti-inflammatory agents (p = .020); increased regular scheduling of aspirin and acetaminophen; and an overall decrease in total drug usage from 7.2 to 4.8 drugs per patient. No effect was noted on the number of analgesics per patient, and the percentage of aspirin or propoxyphene or acetaminophen combinations used. A protocol was established for pain therapy, including a system of stop orders for propoxyphene and codeine.

Aged↗
PubMed2002

Influence of opioid agonists on cardiac human ether-a-go-go-related gene K(+) currents.

We have evaluated the ability of various opioid agonists, including methadone, L-alpha-acetylmethadol (LAAM), fentanyl, meperidine, codeine, morphine, and buprenorphine, to block the cardiac human ether-a-go-go-related gene (HERG) K(+) current (I(HERG)) in human cells stably transfected with the HERG potassium channel gene. Our results show that LAAM, methadone, fentanyl, and buprenorphine were effective inhibitors of I(HERG), with IC(50) values in the 1 to 10 microM range. The other drugs tested were far less potent with respect to I(HERG) inhibition. Compared with the reported maximal plasma concentration (C(max)) after administration of therapeutic doses of these drugs, the ratio of IC(50)/C(max) was highest for codeine and morphine (>455 and >400, respectively), thereby indicating that these drugs have the widest margin of safety (of the compounds tested) with respect to blockade of I(HERG). In contrast, the lowest ratios of IC(50)/C(max) were observed for LAAM and methadone (2.2 and 2.7, respectively). Further investigation showed that methadone block of I(HERG) was rapid, with steady-state inhibition achieved within 1 s when applied at its IC(50) concentration (10 microM) for I(HERG) block. Results from "envelope of tails" tests suggest that the majority of block occurred when the channels were in the open and/or inactivated states, although approximately 10% of the available HERG K(+) channels were apparently blocked in a closed state. Similar results were obtained for LAAM. These results demonstrate that LAAM and methadone can block I(HERG) in transfected cells at clinically relevant concentrations, thereby providing a plausible mechanism for the adverse cardiac effects observed in some patients receiving LAAM or methadone.

Cation Transport Proteins↗
PubMed2002

Expression, purification, biochemical characterization, and comparative function of human cytochrome P450 2D6.1, 2D6.2, 2D6.10, and 2D6.17 allelic isoforms.

Polymorphism at the cytochrome P450 2D6 (CYP2D6) locus is one of the most widely known causes of pharmacogenetic variability in humans. Our goal is to investigate the intrinsic enzymatic differences that exist among active CYP2D6 isoforms to test the hypothesis that these enzymatic differences are substrate-dependent. Active CYP2D6.1, 2, 10, and 17 holo-enzymes were expressed in vitro and purified to a high degree of homogeneity as confirmed with SDS-polyacrylamide gel electrophoresis, CO-difference spectroscopy, and mass spectral analysis. Purified enzyme was reconstituted with lipid and cytochrome P450 reductase in a 2:1 ratio before kinetic analysis. The reaction rate for dextromethorphan (DXM) O-demethylation, DXM N-demethylation, codeine O-demethylation, and fluoxetine N-demethylation catalyzed by each of the variants was determined. The CYP2D6.10 enzyme was the most impaired, exhibiting an estimated enzyme efficiency (as V(max)/K(m)) 50-fold lower for DXM O-demethylation and 100-fold lower for fluoxetine N-demethylation when compared with CYP2D6.1, whereas no measurable catalytic activity was observed for this variant toward codeine. The atypical DXM N-demethylation pathway catalyzed by this variant decreased only 2-fold in comparison. In the case of CYPD6.17, estimated clearances for each metabolite were decreased 6 to 33%. Likewise, the intrinsic clearance of CYP2D6.2 enzyme was consistently decreased for each reaction examined, indicating that the ultra-rapid metabolizer phenotype sometimes associated with this genotype is not a function of the underlying amino acid substitutions. Overall enzyme efficiencies for the metabolism of each substrate therefore decreased in the order of 2D6.1 > 2D6.2 > 2D6.17 > 2D6.10.

Alleles↗
PubMed2005

Comparison of the antinociceptive response to morphine and morphine-like compounds in male and female Sprague-Dawley rats.

Male rats are more sensitive to the antinociceptive effects of morphine than female rats. This difference is seen across several rat strains using a variety of nociceptive stimuli. However, the literature in regard to sex differences in antinociceptive responses to mu-opioids other than morphine is less consistent. The present study was designed to examine whether there is a structure-activity rationale that determines which mu-opioids will show a differential antinociceptive response between male and female rats. A series of morphinans closely related in structure to morphine, namely, codeine, heroin, hydrocodone, hydromorphone, oxymorphone, and oxycodone, were examined for their antinociceptive activity in male and female Sprague-Dawley rats and compared with the structurally unrelated mu-opioid agonists methadone and fentanyl. Antinociception was measured by the warm-water tail-withdrawal assay. The results show that morphine is more potent in males compared with females > hydromorphone = hydrocodone = oxymorphone, but there was no observable sex difference in the antinociceptive potency of codeine, heroin, oxycodone, methadone, or fentanyl. The potency to stimulate guanosine 5'-O-(3-[35 S]thio)triphosphate ([35S]GTPgammaS) binding and binding affinity of the various morphinans was compared in rat glioma C6 cells expressing the rat mu-opioid receptor; relative efficacy was also compared by stimulation of [35S]GTPgammaS binding in slices of rat brain thalamus. The presence of a sex difference in antinociceptive responsiveness was not related to drug potency, efficacy, or affinity. Consequently, it is likely that differential metabolism of the opioid, possibly by glucuronidation, determines the presence or absence of a sex difference.

Analgesics, Opioid↗
PubMed1967

Biosynthesis of the morphine alkaloids.

Tracer experiments, supported throughout by the analogous chemical transformations, have firmly established the biosynthetic sequence tyrosine -->norlaudanosoline --> reticuline --> salutaridine --> salutaridinol-I -->thebaine --> codeine --> morphine in Papaver somniferum. In general, the farther a precursor lies along this sequence, the more efficient its conversion to morphine in the intact plant. Several intermediates remain to be discovered, such as those lying between tyrosine and norlaudanosoline and between thebaine and codeine. Proof that morphine is made only by the reticuline-salutaridine route is still lacking and would require a careful comparison of the rate of morphine synthesis with the turnover rates for the various intermediates. More importantly, detailed knowledge of the mechanism of each biochemical step can come only with isolation of the enzyme system involved. The chemical oxidation of (-)-reticuline, to give salutaridine, can only be accomplished in very low (0.02 percent) yield (15, 26), whereas, even with whole plants, the biological incorporation of reticuline into the morphine alkaloids can reach 8 percent (13). One would like to know just how an enzyme system directs the oxidative cyclization of reticuline in the desired sense. Kleinschmidt and Mothes and Fairbairn and Wassel (27) have shown that the latex isolated from opium poppies is capable of transforming tyrosine into morphine. Perhaps further work with opium latex will provide the key to the remaining problems of morphine biosynthesis.

Morphine↗
PubMed1992

Night pain in arthritis: patients at risk from prescribed night sedation.

To assess the problem of night pain and the use of hypnotic drugs in patients with rheumatic diseases 165 consecutive patients (mean age 58.5 years) were assessed and questioned about night pain and the use of drugs including night sedation. Most of the patients (106 (64%)) were women. A total of 32 (19%) patients were receiving night sedation for a mean duration of 43.9 months. Fourteen patients (13 women) were using these drugs to treat insomnia related to pain. The mean visual analogue pain score for night pain showed a significant difference between those receiving night sedation (5.2) and those who were not (3.7). Of the 70 patients who answered the Stanford Health Assessment Questionnaire (HAQ), those receiving night sedation also had a significantly higher mean score (1.91) than those who were not (1.2), suggesting that patients receiving night sedation were more clinically disabled. Codeine was used by more (34%) patients receiving night sedation than those who were not (18%) suggesting that those receiving night sedation had more pain. These results highlight the need for better pain management in patients with rheumatic diseases to minimise the risk of prescribing addictive drugs such as hypnotic drugs and codeine.

Aged↗
PubMed1975

Analysis of brain uptake and loss or radiotracers after intracarotid injection.

The amount of radioactivity in brain was estimated at different times after intracarotid injection in the pentobarbital-anesthetized rat. Fifteen seconds after injection, six radiolabeled solutes minimally metabolized by brain, 3H2O , isopropanol, nicotine, antipyrine, 3-O-methyglucose, and codeine, left the brain according to first-order kinetics. Two solutes metabolized by brain, lactic acid, and heroin, behaved in a more complex fashion. The behavior of the six nonmetabolized solutes was interpreted satisfactorily by a simple model in which the brain is treated as a single compartment. From the model, uptake at 15 s as a percentage of the dose is linearly related to the permeability when the uptake is low, i.e., 30% or less. In higher uptakes blood flow becomes increasingly important. The efflux rate is similarly related to permeability and blood flow, but additionally it depends inversely on brain space. The exchanges of 3H2O, isopropanol, and nicotine were determined almost solely by blood flow and brain space. Movements of codeine and 3-O-methylglucose depended primarily on permeability and those of antipyrine on both factors.

Animals↗
PubMed1999

Pulmonary inflammation alters the lung disposition of lipophilic amine indicators.

Many lipophilic amine compounds are rapidly extracted from the blood on passage through the pulmonary circulation. The extent of their extraction in normal lungs depends on their physical-chemical properties, which affect their degree of ionization, lipophilicity, and propensity for interacting with blood and tissue constituents. The hypothesis of the present study was that changes in the tissue composition that occur during pulmonary inflammation would have a differential effect on the pulmonary extraction of lipophilic amines having different properties. If so, measurement of the extraction patterns for a group of lipophilic amines, having different physical-chemical properties, might provide a means for detecting and identifying lung tissue abnormalities. To evaluate this hypothesis, we measured the pulmonary extraction patterns for four lipophilic amines, [(14)C]diazepam, [(3)H]alfentanil, [(14)C]lidocaine, and [(14)C]codeine, along with two hydrophilic compounds, (3)HOH and [(14)C]phenylethylamine, after the bolus injection of these indicators into the pulmonary artery of isolated lungs from normal rabbits and from rabbits with pulmonary inflammation induced by an intravenous injection of complete Freund's adjuvant. The pulmonary extraction patterns, parameterized using a previously developed mathematical model, were, in fact, differentially altered by the inflammatory response. For example, the tissue sequestration rate, k(seq) (ml/s), per unit (3)HOH accessible extravascular lung water volume significantly increased for diazepam and lidocaine, but not for codeine and alfentanil. The results are consistent with the above hypothesis and suggest the potential for using lipophilic amines as indicators for detection and quantification of changes in lung tissue composition associated with lung injury and disease.

Algorithms↗
PubMed2003

Attitudes toward opioid use for chronic pain: a Canadian physician survey.

OBJECTIVES: To measure chronic pain patient volumes seen in primary care practice; to determine what medications physicians choose for the treatment of moderate to severe chronic pain; to identify barriers to the use of opioids in the treatment of chronic pain; and to assess physicians' attitudes toward the current management of chronic pain in Canada. DESIGN: A computer-assisted telephone survey of 100 regionally representative Canadian physicians with a defined interest in palliative care (PC, n=30) or noncancer pain (GP, n=70). SETTING: A survey was conducted by Ipsos-Reid in June 2001. Only physicians who met the eligibility criteria of having written 20 or more prescriptions for moderate to severe pain in the preceding four weeks or having devoted 20% of time to palliative care were eligible to participate. RESULTS: In one month, the average number of patients with moderate to severe chronic pain seen by PCs was 94.2; the average seen by GPs was 44.7. The pain experienced by 83.3% of GP patients was noncancer related. For chronic cancer pain, an opioid analgesic was the treatment of choice of 79% of physicians (48% preferred morphine, 21% codeine, 10% other). For moderate to severe chronic noncancer pain, opioids were the first-line treatment of only 32% of physicians (16% preferred codeine, 16% major opioids) because a significant number preferred either non-steroidal anti-inflammatory drugs (29%) or acetaminophen (16%). Thirty-five per cent of GPs and 23% of PCs would never use opioids for noncancer pain, even when described as severe. Chronic pain was deemed by 68% of physicians to be inadequately managed. Almost 60% thought that pain management could be enhanced by improved physician education. Identified barriers to opioid use included addiction potential (37%) and side effects (25%). Seventeen per cent of GPs and 10% of PCs thought that regulatory sanctions limited opioid prescribing. CONCLUSIONS: Even among physicians experienced in chronic pain treatment, there is a reluctance to use opioids for severe nonmalignant pain. One-half of the survey participants believed that there was a need for improved physician education in pain management, including the use of opioids.

Analgesics, Opioid↗
PubMed2001

Somatic Embryogenesis, Rhizogenesis, and Morphinan Alkaloids Production in Two Species of Opium Poppy.

A study of somatic embryogenesis and rhizogenesis and their influence on production of morphinan alkaloids on two species of opium poppy is presented. We identified the ratios of auxin and cytokinin that caused somatic embryogenesis and rhizogenesis in hypocotyl and cotyledons of Papaver somniferum album and Papaver orientale splendidissimum. The hypocotyls and cotyledons both show somatic embryogenesis in Papaver somniferum album whereas only the cotyledons were embryogenic in Papaver orientale splendidissimum. For rhizogenesis, the most important response is on the cotyledons and leaves in these two species. Histology showed characteristic stages of somatic embryo: Globular, cotyledonous, and heart cotyledonary. High performance liquid chromatography analysis showed that the roots of both species synthesized codeine, thebaine, and papaverine. Morphine was only detected in aerial parts of Papaver somniferum album. Codeine and thebaine were detected in the rhizogenous but no embryonic callus. These results suggest that root organogenesis is causally related to alkaloid biosynthesis.

Journal Article↗
PubMedDate not supplied

Factors influencing immediate responses to intradermal allergen administration in patients with respiratory allergy.

BACKGROUND: Immediate skin reactions to allergens are influenced by several factors, such as the amount of administered allergen, the level of specific IgE, releasability of mast cells and hyperresponsiveness of the target organ. METHODS: For the evaluation of factors influencing immediate skin response to intradermal allergen administration, we measured the wheal size 15 min after intradermal injection of 0.01-0.02 ml of the following agents: whole-body extract of Dermatophagoides farinae, 1,000 allergy units/ml; histamine, 0.1 mg/ml, and codeine sulfate, 0.09% in saline, and determined total IgE level, specific IgE and IgG subclass antibodies to D. farinae in 53 patients with respiratory allergy. RESULTS: Multiple regression analysis for factors influencing wheal size after intradermal injection of D. farinae, specific IgE antibody level to D. farinae and wheal size after intradermal administration of histamine showed statistically significant results (R2 = 0.42739, p = 0.0000; R2 = 0.50243, p = 0.0185, respectively). Multiple regression analysis for factors influencing wheal size after intradermal administration in the group with high levels of specific IgE to D. farinae (RAST class 3 or more) showed that wheal size after intradermal administration of codeine was the only factor exerting a statistically significant influence (p = 0.0119). CONCLUSION: Based on the above results, we can state that immediate responses to intradermal allergen administration were influenced by the level of specific IgE and hyperresponsiveness of the target organ to histamine, but that the immediate skin allergic responses in the presence of high levels of specific IgE were partially but significantly influenced by the releasability of skin mast cells.

Adult↗
PubMed1999

Patient-controlled analgesia in postoperative cardiac surgery.

The purpose of this study was to assess, in the early postoperative period of cardiac surgery, the efficacy of patient-controlled analgesia (PCA) versus nurse-administered intravenous morphine followed by oral acetaminophen with or without codeine. Patients undergoing coronary bypass and/or valvular surgery were recruited. All were under 75 years of age and were in stable angina with no ischaemic attacks within the last three months. Visual analog scores (VAS) were used for pain assessment. Pulmonary function tests were done preoperatively and measured every six hours after surgery until discharge from the intensive care unit. Patients allocated to the PCA group received morphine intravenously by a PCA Plus Micro Delivery Device for at least 48 hours. Patients entered into the nurse-administered intravenous morphine group received intravenous morphine followed by oral acetaminophen with or without codeine in 24 to 36 hours according to the clinical assessment of the critical care nurse. The data showed that the quality of pain control and pulmonary function were comparable in both groups. The equipotent morphine dosage requirements were also not statistically different. It was concluded that there was no significant advantage in using PCA routinely in the early postoperative period after cardiac surgery. Furthermore, repetition of PCA instructions was often required during the study period.

Acetaminophen↗
PubMedDate not supplied

An evaluation of pre- and postoperative nonsteroidal antiinflammatory drugs in patients undergoing knee arthroscopy. A prospective, randomized, double-blinded study.

The potential benefits of a nonsteroidal antiinflammatory drug to 67 patients undergoing knee arthroscopy were evaluated in a prospective, randomized, placebo-controlled, double-blinded study. Group A received the drug (diclofenac, 75 mg twice daily) for 3 to 5 days before and for 7 days after surgery. Group B received a placebo preoperatively and the drug postoperatively. Group C received a placebo at both times. Codeine was available postoperatively for all patients if needed. Outcomes reported by the subjects included pain, crutch use, and return to activities. Outcomes assessed by physicians included knee effusion, range of motion, and gait. Knee flexion and extension strengths were measured isokinetically pre- and postoperatively. Pain scores on the 1st postoperative day were higher in Group C than in Group A. Pain scores at all other time points were not significantly different in the three treatment groups. Groups A and B required less codeine during the first 72 hours after surgery than Group C (mean, 2.9 +/- 1.0 versus 6.8 +/- 1.0 pills). Recovery of function, recovery of strength, and physical examination parameters were not significantly different in the three treatment groups. Diclofenac was an effective analgesic in the immediate postoperative period. Recovery from arthroscopy, however, was not enhanced by taking the drug.

Adolescent↗
PubMed2001

Successful withdrawal from analgesic abuse in a group of youngsters with chronic daily headache.

Abuse of ergotamine and analgesics is common in adults. It coexists with headache and can also induce headaches. Ten to 15% of patients attending headache clinics and 1% of the general population suffer from chronic daily headache due to medication misuse. Indeed, this phenomenon was recently regarded as an epidemic. Nonetheless, analgesic-induced headache in children and adolescents was first reported in 1998. We report on our experience with children and adolescents with daily or almost-daily headache concomitant with daily or almost-daily analgesic intake. Over a period of 3 years, we evaluated 26 children (19 girls and 7 boys) with chronic daily or near-daily headache related to daily analgesic intake. The mean age of the group was 14.2 years (range, 12-18), and the mean headache history duration was 1.6 years (range, 3 months to 4 1/2 years). The mean number of headache days per month was 28.1 (range, 19-31). All patients had no history of migraine prior to the chronic headache phase according to the International Headache Society criteria. They were using at least one dose of analgesic drug for each headache, whereas 16 were using analgesic drugs daily. The weekly analgesic intake averaged 28.1 tablets (range, 19-41). The majority abused simple analgesics. Twenty-one took acetaminophen alone. Five took a combination; four took a compound containing acetaminophen, caffeine, and codeine; and the fifth patient took a compound containing aspirin, caffeine, and codeine. All patients were informed about the phenomenon of medication-induced headache and were encouraged to achieve drug withdrawal. Withdrawal led to complete cessation of all headaches in 20 patients. In 5 patients, the daily headache resolved; however, they suffered from intermittent episodic migraine attacks, which were frequent enough in 3 to initiate prophylactic medication. One adolescent continued to have daily headache. Analgesic-induced headache does occur in adolescents. Successful withdrawal from the offending analgesics was achieved without hospitalization or significant interference with daily life and with complete disappearance of the induced chronic daily headache in 25 of 26 patients.

Adolescent↗
PubMed1987

Effects of renal insufficiency on the pharmacokinetics and pharmacodynamics of opioid analgesics.

The disposition and pharmacologic activities of morphine, meperidine, methadone, propoxyphene, dihydrocodeine, and codeine are reviewed. Dose-related toxicities of these opioid analgesics include mental obtundation, respiratory depression, and hypotension. Furthermore, convulsions have been associated with normeperidine and cardiac toxicities with norpropoxyphene. Hepatic metabolism is the primary route of elimination, except for methadone, for which there is also significant renal excretion. Although the pharmacokinetics of morphine are unchanged in renal insufficiency, accumulation of active metabolites may lead to narcosis. Similar accumulation of normeperidine and norpropoxyphene, metabolites of meperidine and propoxyphene, respectively, as well as propoxyphene itself, and dihydrocodeine and codeine may explain reports of adverse reactions in patients with impaired renal function. A high index of suspicion of opioid-induced toxicities should be maintained in patients who have renal dysfunction and receive opioids.

Humans↗