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Drugs and falls in older people: a systematic review and meta-analysis: II. Cardiac and analgesic drugs.

OBJECTIVES: To evaluate critically the evidence linking specific classes of cardiac and analgesic drugs to falls in older people. DESIGN: Fixed-effects meta-analysis. DATA SOURCES: English-language articles in MEDLINE (1966 - March 1996) indexed under accidents or accidental falls and aged or age factors; bibliographies of retrieved papers. STUDY SELECTION: Systematic evaluation of cardiac or analgesic drug use and any fall in people aged 60 years and older. DATA EXTRACTION: Study design, inclusion and exclusion criteria, setting, sample size, response rate, mean age, method of medication verification and fall assessment, fall definition, and the number of fallers and nonfallers taking specific classes of cardiac and analgesic drugs. RESULTS: Twenty nine studies met inclusion criteria. None were randomized controlled trials. For one or more falls, the pooled Odds Ratio (95% Confidence Interval) was 1.08 (1.02-1.16) for diuretic use, 1.06 (0.97-1.16) for thiazide diuretics, 0.90 (0.73-1.12) for loop diuretics, 0.93 (0.77-1.11) for beta-blockers, 1.16 (0.87-1.55) for centrally acting antihypertensives, 1.20 (0.92-1.58) for ACE inhibitors, 0.94 (0.77-1.14) for calcium channel blockers, 1.13 (0.95-1.36) for nitrates, 1.59 (1.02-2.48) for type Ia antiarrhythmics, and 1.22 (1.05-1.42) for digoxin use. For analgesic drugs, the pooled OR was 0.97 (0.78-1.20) for narcotic use, 1.09 (0.88-1.34) for nonnarcotic analgesic use, 1.16 (0.97-1.38) for NSAID use, and 1.12 (0.80-1.57) for aspirin use. There was no statistically significant heterogeneity of pooled odds ratios. There were no differences between the pooled odds ratios for studies with mean subject age <75 versus > or =75 years old or for studies in communities with <35% versus > or =35% fallers. In studies of the relationship between psychotropic, cardiac, or analgesic drugs and falls, subjects reporting the use of more than three or four medications of any type were at increased risk of recurrent falls. CONCLUSION: Digoxin, type IA antiarrhythmic, and diuretic use are associated weakly with falls in older adults. No association was found for the other classes of cardiac or analgesic drugs examined. The evidence to date, however, is based solely on observational data, with minimal adjustment for confounders, dosage, or duration of therapy. Older adults taking more than three or four medications were at increased risk of recurrent falls. As a result of the incidence of falls and their consequences in this population, programs designed to decrease medication use should be evaluated for their impact on fall rates.

Accidental Falls↗

Efficacy of intra-muscular analgesics for acute pain in sheep.

The analgesic action of intramuscularly injected buprenorphine, methadone, flunixin meglumine and xylazine was examined in sheep, using algesimetry based on a leg withdrawal response to an electrical stimulus. No analgesic response was detected for buprenorphine, methadone or flunixin meglumine. Only the alpha 2-adrenoceptor agonist, xylazine, produced an analgesic response. The current required to elicit a response increased by 170% (4.5 +/- 0.43 mA to 12.23 +/- 1.14 mA; mean +/- SE) after a dose of 0.05 mg/kg xylazine; by 180% (4.73 +/- 0.3 mA to 13.28 +/- 2.35 mA) after 0.1 mg/kg and by 510% (4.52 +/- 0.29 mA to 27.63 +/- 3.89 mA) after 0.2 mg/kg. Intramuscular xylazine appears to be an effective analgesic agent for acute pain in the sheep and further investigation into ideal administration regimens and dosage may provide more detailed information on relationships between dose, analgesic and sedative effects. The findings also suggest that some common analgesic agents, and opioids in particular, may be ineffective for the management of acute pain in sheep and that any analgesic should be administered only on the basis of its proven efficacy in that species.

Acute Disease↗

The analgesic domain of interferon-alpha2b contains an essential proline(39) residue.

OBJECTIVE: It has been demonstrated that there are structural and functional similarities between interferon-alpha (INF-alpha) and endorphins. We have reported that there are distinct domains in the IFN-alpha molecule that mediate immune and analgesic effects, respectively, and that the opioid-like analgesic effect of IFN-alpha is mediated by the mu opioid receptor, thus inferring that the analgesic domain of IFN-alpha consists of Tyr(122) and the residues around Tyr(122) in the tertiary structure. The aim of this work was to further explore the molecular basis for the analgesic domain of IFN-alpha. METHODS: By using site-directed mutagenesis, the structure of IFN-alpha was changed and a mutant of IFN-alpha was obtained. Then, the antiviral activity and opioid-like analgesic activity of IFN-alpha were measured. RESULTS: When the Pro(39) residue of IFN-alpha, which is located close to the Tyr(122) residue in the tertiary structure, was mutated to Gly, the analgesic activity of this mutant was lost completely, but the antiviral activity of IFN-alpha was maintained compared with wild-type IFN-alpha. CONCLUSIONS: Combining the sequence of the endomorphin, it is suggested that the Pro(39) residue is one of the constituents of the analgesic domain of IFN-alpha and contributes to IFN-alpha binding to the mu opioid receptor.

Analgesics↗

Analgesic rebound headache in children and adolescents.

For more than a decade, the frequent use of analgesics has been recognized to lead to daily headaches in adults. To date, no studies on the occurrence of analgesic rebound headache have been done on the pediatric population. We retrospectively reviewed all charts of patients with the diagnosis of headache seen in our pediatric headache clinic between January 1996 and May 1997. Among the 98 patients seen, 46 (47%) suffered from daily or near daily headaches; 30 of them were consuming daily analgesics. Twenty-four patients (mean age 12.1 years, and mean follow-up 6.2 months) successfully discontinued their analgesics. Twenty-two patients were also placed on amitriptyline. A significant reduction in the frequency (80%), severity (47%), and number of school days missed (74%) were seen. In conclusion, this data is comparable to previous observations reported in adults, and suggests that the daily use of analgesics might result in daily or near daily headaches in the pediatric population. Discontinuing daily analgesics, with the concomitant use of amitriptyline, is an effective treatment for analgesic rebound headache in this population.

Adolescent↗

[Relationship between biogenic amines and analgesic action of difenamizole in heat induced reflexes].

Effects of drugs that modify catecholaminergic or tryptaminergic mechanisms were determined in experimental animals regarding the analgesic action of difenamizole, morphine, and aminopyrine. Analgesia was assessed by the hot plate method in mice and the hot water induced tail withdrawal reflex in rats. Both 5-hydroxytryptophan (5-HTP) and L-dopa potentiated the analgesic action of morphine, but antagonized the action of difenamizole in the hot plate test. p-Chlorophenylalanine (pCPA), alpha-methyl-p-tyrosine (alpha-MT), and reserpine antagonized the effect of morphine as assessed by this same test. alpha-MT potentiated the analgesic action of difenamizole. The analgesic action of aminopyrine was hardly modified in the hot plate method by pretreatment with 5-HTP, pCPA, L-dopa, and alpha-MT. In rats, 5-HTP antagonized the effect of morphine, while pCPA, L-dopa, and alpha-MT caused no appreciable change in the analgesic action of morphine in the hot water induced tail withdrawal reflex. The effect of difenamizole was not modified by pretreatment with these monoamine-related drugs. On the other hand, brain 5-hydroxytryptamine content was increased by pretreatment with 5-HTP in both tests. These results suggest that the analgesic action of difenamizole and morphine, as measured in the hot plate test in mice, may be mediated by catecholamines and 5-hydroxytryptamine, but that other mechanisms may be involved in the hot water induced tail withdrawal relfex in rats. In addition, the biogenic amines may play a different role depending on the type of analgesic.

5-Hydroxytryptophan↗

Antiinflammatory, analgesic and hypoglycemic effects of Mangifera indica Linn. (Anacardiaceae) stem-bark aqueous extract.

Previous studies in our laboratories and elsewhere have shown that some members of Anacardiaceae family possess antiinflammatory, analgesic and hypoglycemic effects in man and mammalian experimental animals. The present study was, therefore, undertaken to examine the antiinflammatory, analgesic and antidiabetic properties of the stem-bark aqueous extract of Mangifera indica Linn., M. indica a member of the Anacardiaceae family, in rats and mice. The stem-bark powder of M. indica was Soxhlet extracted with distilled water and used. The analgesic effect of the plant's extract was evaluated by the hot-plate and acetic acid test models of pain in mice, while the antiinflammatory and antidiabetic effects of the stem-bark extract were investigated in rats, using fresh egg albumin-induced paw edema, and streptozotocin (STZ)-induced diabetes mellitus, respectively. Morphine (MPN, 10 mg/kg i.p.), diclofenac (DIC, 100 mg/kg i.p.), and chlorpropamide (250 mg/kg p.o.) were used respectively as reference analgesic, antiinflammatory, and hypoglycemic agents for comparison. M. indica stem-bark aqueous extract (MIE, 50-800 mg/kg i.p.) produced dose-dependent and significant (p<0.05-0.001) analgesic effects against thermally and chemically induced nociceptive pain stimuli in mice. MIE (50-800 mg/kg i.p.) also significantly (p<0.05-0.001) inhibited fresh egg albumin-induced paw edema, and caused significant (p<0.05-0.001) hypoglycemic effects in rats. It is suggested that the analgesic effects of MIE (50-800 mg/kg i.p.) may be peripherally and centrally mediated. The different chemical constituents of the plant, especially the polyphenolics, flavonoids, triterpenoids, mangiferin, and other chemical compounds present in the plant may be involved in the observed antiinflammatory, analgesic, and hypoglycemic effects of the plant's extract. However, the results of this experimental animal study lend pharmacological credence to the suggested folkloric uses of the plant in the management and control of painful, arthritic and other inflammatory conditions, as well as in the management of adult-onset type 2 diabetes mellitus in some rural African communities.

Albumins↗

The optimal analgesic dose of rofecoxib: Overview of six randomized controlled trials.

BACKGROUND: Rofecoxib, which specifically inhibits cyclooxygenase-2, is indicated for relief of the signs and symptoms of osteoarthritis and for the management of acute pain in adults. The authors present an overview of six placebo-controlled trials designed to evaluate the single-dose analgesic efficacy of a range of doses of rofecoxib in the treatment of postoperative dental pain. METHODS: The six studies included doses of rofecoxib ranging from 7.5 to 500 milligrams. Maximal analgesic doses of a nonsteroidal anti-inflammatory drug, or NSAID, either naproxen sodium (550 mg) or ibuprofen (400 mg), were used as active comparators in each study. Analgesic efficacy was assessed with the use of validated self-administered questionnaires. The primary endpoint in each study was the total pain relief over the eight-hour postdose period. Additional endpoints were used to characterize the onset of analgesia and peak analgesic effect. RESULTS: The results of these studies demonstrated that the efficacy of rofecoxib was dose-related, with 50 mg being consistently more effective than placebo for all measures of analgesic efficacy. Moreover, 50 mg was the lowest dose that reproducibly demonstrated an analgesic effect comparable to the effect of maximum single analgesic doses of NSAIDs. CONCLUSION: The results of these studies support the recommended dose of 50 mg of rofecoxib once daily for the management of pain. CLINICAL IMPLICATIONS: Rofecoxib, at a dose of 50 mg, is effective in the management of postoperative dental pain.

Adolescent↗

Pain management in the emergency department: patterns of analgesic utilization.

OBJECTIVE: To compare the use of analgesia in children to adults in 3 different emergency department (ED) settings. METHODS: Forty adult and 40 pediatric ED charts were randomly selected for review at each of 3 institutions: an academic medical center with separate pediatric and adult EDs (SEP ED), a community academic medical center with a combined adult and pediatric ED (COMB ED), and a community hospital with a combined ED (COMTY ED). All patients presenting to the EDs from July 1993 to June 1994 within 12 hours of an isolated long bone fracture were eligible for inclusion. Data were collected on demographics, training of providers, analgesic use and dosing in the ED and on discharge, and time from triage to analgesic use. RESULTS: The mean pediatric and adult ages were 8.7 and 38.3 years, respectively. Overall, 152/240 (63%) patients received some form of analgesia in the ED, with the COMTY ED (41/80; 51%) offering significantly less analgesia than the COMB ED (58/80; 73%), but not the SEP ED (53/80; 66%). Pediatric patients (64/120; 53%) received significantly less analgesia in the ED than adult patients (88/120; 73%). This difference was significant at the COMB ED (pediatric 23/40; 58% vs adult 35/40; 88%) and COMTY ED (pediatric 15/40; 38% vs adult 26/40; 65%), but not at the SEP ED (pediatric 26/40; 65% vs adult 27/40; 68%). 195/240 (81%) patients received discharge pain medication. There were no differences between pediatric (93/120; 78%) and adult (102/120; 85%) discharge analgesic prescribing practices. Although there was no difference in appropriateness of analgesic doses in the ED, pediatric patients (20/74; 27%) were more likely than adult patients (3/88; 3%) to receive inadequate doses of analgesics on discharge from the ED. CONCLUSIONS: ED analgesia continues to be used less frequently in the pediatric compared with the adult population. Inadequate dosing of discharge analgesic medication in children is a significant problem. Patterns of analgesic utilization may differ in different types of ED settings.

Academic Medical Centers↗

Analgesic abuse in the elderly. Renal sequelae and management.

Nephropathy caused by the use of 'classical' analgesics [paracetamol (acetaminophen), salicylates and pyrazolone derivatives] and renal impairment associated with nonsteroidal anti-inflammatory drugs (NSAIDs) are important health problems in the elderly. Classical analgesic nephropathy is a chronic renal disease characterised by renal papillary necrosis and chronic interstitial nephritis. The nephropathy is caused by the excessive consumption of analgesic mixtures containing at least 2 antipyretic analgesics combined with caffeine and/or codeine. The use of NSAIDs is associated with a wide range of tubular, interstitial, glomerular and vascular renal lesions. Despite the well-characterised acute biological effects of NSAIDs on the kidney, there is only limited evidence that they are associated with an increased risk of chronic renal failure. Classical analgesic toxicity can be effectively prevented by limiting the availability of over-the-counter analgesic mixtures containing 2 analgesic compounds in combination with potentially addictive substances (e.g. caffeine and/or codeine). In the elderly in particular, the prolonged, regular use of NSAIDs should be discouraged. Patients starting NSAID therapy should be monitored regularly and drug interactions should be avoided.

Aged↗

Environmental factors and chronic gastric ulcer. A case control study of the association of smoking, alcohol, and heavy analgesic ingestion with the exacerbation of chronic gastric ulcer.

The aim of this case control study was to define the strength of the associations of smoking, alcohol, and heavy analgesic ingestion with chronic gastric ulcer (GU). Ninety-nine patients were interviewed about smoking, alcohol, and analgesic ingestion for the 6 months before exacerbation of their chronic GU. The 180 non-ulcer community control subjects were frequency-matched with the patients for the characteristics of age, sex, and social status. Smoking, alcohol, and heavy analgesic ingestion were studied when present as sole factors and in combinations. Their associations with GU were measured by the odds ratio (OR) and the adjusted odds ratio (AOR). Smoking in male patients (OR 15.4) and heavy analgesic ingestion in female patients (OR 23.4) were significant as sole factors. Smoking plus heavy analgesic ingestion was significant in female patients (OR 10.0), and the combination of all three factors was significant in male patients (OR 13.0) and in female patients (OR 6.3). Smoking had significantly increased AORs of 3.3 in male patients and 3.5 in female patients; alcohol had a significantly decreased AOR of 0.4 in female patients; and heavy analgesic ingestion was significantly increased in female patients (AOR 7.2). It is concluded that smoking in all patients and heavy analgesic ingestion in female patients are risk factors for chronic GU. Alcohol, however, does not appear to be a risk factor.

Adult↗

Analgesic use disorders among orthopedic and chronic pain patients at a rehabilitation clinic.

Interviews were conducted with 265 orthopedic and chronic pain patients, using a structured diagnostic instrument (ADDIS/SUDDS) concerning their use of analgesics. Twenty-two percent of the patients met criteria for analgesic use disorders in accordance with DSM-III-R; 18.5% fulfilled DSM-IV criteria. Dextropropoxyphene was the most common analgesic prescribed and was used by 47% of the patients who met criteria for analgesic use disorders. It is concluded that patients with chronic pain using narcotic analgesics are at considerable risk of developing analgesic use disorders. Assessment of the use of analgesics should be offered to pain patients taking narcotic drugs.

Adult↗

Analgesic effect of endomorphin-1.

AIM: To study the analgesic effect of endomorphin-1 (EM-1). METHODS: The experiment was performed in rats and mice to study the analgesic effect of intraperitoneal (ip) injection of EM-1 with tail stimulation-vocalization test, writhing test, adjuvant arthritis, and neuropathic pain model and to compare it with the analgesic effects produced by intracerebroventricular (icv) and intrathecal (it) administrations. RESULTS: 1) EM-1 raised the pain threshold dose-dependently in tail stimulation-vocalization test in rats and inhibited the writhing responses induced by ip acetic acid in mice. EM-1 also decreased the hyperalgesia in both adjuvant arthritis and neuropathic pain model. 2) The analgesic effect induced by central (icv and it) administration of EM-1 was faster and more powerful than that induced by peripheral (ip) administration. 3) The analgesic effect of EM-1 was reversed by naloxone (opioid receptor antagonist), as well as by cyprodime (mu-opioid receptor selective antagonist). Repeated administrations of EM-1 induced tolerance. CONCLUSION: EM-1 had a definite analgesic effect and the analgesic effect of EM-1 was mediated by central mu-opioid receptor.

Analgesics, Opioid↗

The analgesic effect of nalbuphine and its long-acting prodrug, nalbuphine pivalate, in rats.

BACKGROUND: Nalbuphine is an opioid-analgesic with agonist-antagonist properties. Recently, we have synthesized a nalbuphine prodrug, nalbuphine pivalate. The aim of the present study was to evaluate the analgesic effect and the analgesic duration of this prodrug. METHODS: Forty-eight male Sprague-Dawley rats (4 groups, n = 12 in each group) were used. Rats in group 1 received nalbuphine HCl 25 mumol/kg (in saline) intramuscular injection; rats in group 2 received nalbuphine pivalate 25 mumol/kg (in sesame oil) intramuscular injection, whereas those in groups 3 and 4 received saline and sesame oil respectively. The analgesic effects of testing agents were evaluated using the cold ethanol tail-flick test (-30 degrees C). RESULTS: Both nalbuphine HCl and nalbuphine pivalate demonstrated significant analgesic effects. The analgesic duration of nalbuphine HCl was 2 h while that of nalbuphine pivalate was 30 h. CONCLUSIONS: Nalbuphine pivalate has a very long duration of analgesic action. This fascinating finding is worth further evaluation.

Analgesics, Opioid↗

Diagnostic criteria of analgesic nephropathy in patients with end-stage renal failure: results of the Belgian study.

Diagnostic criteria of analgesic nephropathy with well-defined sensitivity and specificity are not available. During a 2-year period all new patients (n = 273) starting renal replacement therapy in 13 Belgian dialysis units were investigated aiming to select diagnostic criteria of analgesic nephropathy with acceptable performance. Using several interview techniques, a history of analgesic abuse was found in 31% of the patients. Analgesic abusers presenting a clear non-analgesic-related renal diagnosis were excluded from analysis (n = 25). Comparing the remaining abusers (n = 60) and patients without a history of analgesic abuse (n = 188) it was found that renal imaging investigations (sonography plus tomography), showing a decrease in length combined with bumpy contours of both kidneys, presented a sensitivity of 90% and a specificity of 95%. The additional finding of signs of renal papillary necrosis resulted in an overall sensitivity of 72% and a specificity of 97%, giving a positive predictive value of 92%. Other signs frequently mentioned in the literature (hypertension, anaemia, sterile pyuria, bacteriuria, proteinuria) showed insufficient sensitivity and/or specificity to be of help for diagnosing analgesic nephropathy in end-stage renal failure (ESRF) patients starting renal replacement therapy.

Adult↗

Cognitive status and analgesic provision in nursing home residents.

BACKGROUND: Although it is becoming acknowledged that pain management is generally poor for older people, little is known about pain management for nursing home residents in the United Kingdom, and the specific problems for those with cognitive impairments. AIMS: This section of a larger study of pain aimed to explore analgesic prescription and administration according to nursing home residents' cognitive status. DESIGN OF STUDY: A survey of nursing home residents and their medication documentation. SETTING: The sample included 113 nursing home residents from 15 nursing homes in large city in the north of England. METHOD: Residents' cognitive status was assessed using the mini-mental state examination (MMSE). Pain was measured with a four-point verbal rating scale and a 10-point horizontal numeric rating scale. Residents' medications--including name, dose, and frequency of administration--were noted, as well as provision within the previous 24 hours. RESULTS: There were no statistically significant differences in pain scores according to level of cognitive impairment. The prescription and administration of opioid and non-opioid analgesics were highest for residents with low cognitive impairment; these decreased as impairment increased. Those who were prescribed neither opioid nor non-opioid analgesics had significantly lower MMSE scores than those who were. A low MMSE score indicates a high level of cognitive impairment. CONCLUSION: It is not clear why those with greater cognitive impairment received fewer analgesics than others. More research is needed into the relationships between pain assessment, pain experience, cognitive impairment, and analgesic provision. It is likely that improvements in carers' knowledge of pain assessment and the risks and benefits of commonly used analgesics could improve analgesic provision.

Aged↗

Acute analgesic effect of loperamide as compared to morphine after intrathecal administration in rat.

Loperamide, a mu opioid receptor agonist, which is commonly used as an antidiarrhoeal agent has been reported to possess analgesic activity after intrathecal administration. However, the exact analgesic profile, i.e., onset, duration and intensity of analgesia in relation to morphine is not fully known. In the present study, the acute analgesic effect of loperamide (5 microg) was compared with that of morphine (5 microg) and morphine + loperamide (5 microg of each) using the tail flick method after intrathecal administration. Naloxone (5 mg/kg) reversibility of the analgesic effect was also studied. The analgesic response of loperamide was significantly higher than morphine. Even after 22 hr, maximum possible effect was greater than 49%. Naloxone partially antagonized the analgesic effect of loperamide. This suggested that loperamide may be acting through blockade of Ca2+ channels besides activating mu opioid receptors. Loperamide may prove to be a better substitute for morphine as spinal analgesic.

Analgesics↗

Perioperative use of analgesics in dogs and cats by Canadian veterinarians in 2001.

A random sample of 652 Canadian veterinarians was surveyed to determine perioperative use of analgesics in dogs and cats following common surgeries. The response rate was 57.8%. With the exception of taildocking in puppies, at least 85% of animals received preincisional analgesics, and 30% to 98.1% received postincisional analgesics. A similar survey was conducted in 1994; since then, analgesic usage has increased markedly, as have ratings of the pain caused by different surgeries. In 2001 most veterinarians (62%) used at least 2 classes of analgesic perioperatively. However, strong opioids, local anesthetics, and alpha-2 agonists were underused, and there was an overreliance on weak opioids (butorphanol, meperidine). Up to 12% of veterinarians did not use any analgesics. Nationally, this may have affected many animals monthly; for example, approximately 6000 dogs or cats undergoing ovariohysterectomy. Continuing education (provincial level) and review articles were considered effective ways to inform veterinarians about optimal analgesic practices.

Analgesics↗

[Headache caused by analgesic and/or ergotamine abuse].

Headache induced by ergotamine-abuse was described 40 years ago. More recently there is ample evidence suggesting that chronic headache may also be provoked by analgesic abuse. A recent Classification of the International Headache Society has defined this kind of headache as an autonomous disease. It consists in a daily chronic headache with paroxysmal attacks associated with daily or almost daily assumption of analgesics and/or ergotamine. It is debated whether the term "abuse" or "dependence" is correct. Almost 5% of patients of the Headache Centres in Italy were found to be drug abusers. Most of these patients originally suffered from migraine. The therapeutic approach consists in hospitalization, withdrawal of analgesics and/or ergotamine, treatment of the withdrawal headache (which appears within 48 hours and lasts even 1-2 weeks) and finally in a prophylactic therapy. Although several treatments have been suggested for the abstinence syndrome, only fluid replacement, antiemetics, hypnotic-sedative drugs and rarely mild analgesics are necessary. A review of the literature shows the following success rates in the relief of the headache: above 50% relief in more than 60% of patients within a follow up period of 1 to 3.5 years as mean. Even if caffeine and barbiturates, which are often contained in the analgesic and ergotamine preparations, might be considered the cause of the abuse and withdrawal syndrome, they don't seem to play a fundamental role in this syndrome. An impairment of the central antinociceptive system was hypothesized to be involved in the pathogenesis of the headache associated with analgesic and/or ergotamine abuse. Recently there has been evidence of a possible hyposensitivity of the adrenergic and serotoninergic receptors of the central nervous system. It is still to be proved whether drug abuse is the cause or the consequence of the headache chronicization. The remarkable improvement of headache after analgesic withdrawal suggests a causal factor.

Analgesics↗