Opioids

Abstract

Introduction

Pain is an unpleasant, subjective, sensory and emotional experience usually associated with actual or potential tissue damage. The pain experience involves a series of complex processes: transduction, transmission, modulation, and perception. Transduction is the conversion of a noxious stimulus into a coded electrical message at the nerve terminal. Message transmission, modulation, and perception occur within the central nervous system (CNS). Pain has three different components: sensory-discriminative, affective-motivational, and cognitive-evaluative.

Positron emission tomography (PET) studies of the human brain during acute pain suggest that sensory, affective and other dimensions of pain are processed in parallel by different parts of the nociceptive system. The lateral nociceptive system, which projects through specific lateral thalamic nuclei, fully accounts for the sensory-discriminative capacity of pain perception. The affective-motivational component of pain is associated with the medial nociceptive system, which, in turn, is connected to the limbic system. Most PET studies of acute pain show activation of the anterior cingulate cortex, a functionally heterogeneous brain area that is implicated in the integration of affect, cognition, and response selection in addition to aspects of social behaviour. Passive functions (emotion, attention) are represented more frontally, whereas a premotor part of the anterior cingulate cortex is situated more posteriorly, below the supplementary motor area (1).

Within the CNS, inhibitory and excitatory pathways modulate pain transmission and perception. The neurotransmitters that are involved in these pathways include norepinephrine, serotonin, and the endogenous opioid peptides. The opiate peptide receptors are the targets for pharmacologic treatment of pain using natural or synthetic exogenous opioid drugs. This review specifically examines the chemistry, biology, and clinical effectiveness of the opioids in treating head pain.

Opioids

‘Among the remedies which it has pleased almighty God to give to man to relieve his sufferings, none is so universal and efficacious as opium’ (2).

Opium is the Greek term for the juice of the poppy plant. Opiates are drugs derived from opium. They can be chemically divided into two groups: phenanthrene (morphine, codeine, and thebaine) and benzylisoquinolines (papaverine and noscapine, which both lack morphine-like properties) (3). Opioid is a more inclusive term, applying to all agonists or antagonists with morphine-like activity, such as derivatives of opium (opiates) or endogenous or synthetic opioid peptides (4). The term narcotic is derived from the Greek word for stupor; however, it is no longer used pharmacologically because of its pejorative legal meaning. Three families of endogenous opioid peptides, each derived from a different polypeptide precursor, have been identified: the enkephalins (from proenkephalin), the endorphins (from pro-opiomelanocortin), and the dynorphins (from prodynorphin). In addition, there is good evidence for the presence of endogenous morphine and codeine. Morphine- and codeine-like substances have been isolated from the brain of several species, and biosynthetic pathways for morphine production, similar to that used by the opium poppy, have been demonstrated in mammals.

Receptors

There are four distinct opioid receptor types: μ, δ, κ and the ‘opioid-like orphan receptor’ (5–7). It is no longer believed that there is a sigma opioid receptor. The μ receptor, important in sensory processing, including the modulation of nociceptive stimuli, extrapyramidal functioning and limbic and neuroendocrine regulation, has three subtypes: a high-affinity μ₁, a low-affinity μ₂, and a newly described μ₃ subtype (6). Morphine and other morphine-like opioid agonists produce analgesia primarily through μ-receptor activation, which also produces respiratory depression, miosis, reduced gastrointestinal motility, and feelings of well-being (euphoria) (8). The supraspinal mechanisms of analgesia produced by μ-opioid agonist drugs are thought to involve the μ₁ receptor, whereas spinal analgesia, respiratory depression, and the effects of opioids on gastrointestinal function are associated with the μ₂ receptor (4). The μ₃ receptor (another splice variant of the receptor) binds opioid alkaloids such as morphine, but has exceedingly low or no affinity for the naturally occurring endogenous opioid peptides. The μ₃ receptor occurs in macrophages, astrocytes, and endothelial cells and may be involved in immune processes. The μ₃ receptor is believed to be coupled to constitutive nitric oxide (NO) release (9). The endogenous ligand for this receptor may be morphine or codeine, which have been found to be present in vertebrate tissues, including the nervous system (6, 9–11).

There are three κ receptor subtypes (Table 1). Dynorphin A is the natural ligand for the κ₁ receptor, which elicits spinal analgesia. The role of the κ₂ receptor is unknown. The κ₃ receptor is the dominant brain opioid receptor. Selective κ receptor agonists continue to produce analgesia in animals who have been made tolerant to μ agonists. κ₁ receptor agonists act primarily in the spinal cord and cause less intense miosis and respiratory depression than do μ agonists. κ₃ receptor analgesia is mediated supraspinally. Instead of euphoria, κ agonists produce dysphoric, psychotomimetic effects (disoriented and/or depersonalized feelings) (4, 12).

TABLE 1

Opioids

Receptor	Endogenous ligand	Agonist	Antagonist
Mu	Beta-endorphin	Morphine	Naloxone
μ₁, μ₂, μ₃
Delta	Enkephalin		Naloxone
δ₁, δ₂
Kappa	Dynorphin	Butorphanol	Naloxone
κ_1, κ_2, κ₃
Orphan	OFQ/N

Two subtypes of the δ receptor, whose natural ligand is the enkephalins, have been identified. The consequences of stimulating δ-opioid receptors with morphine and morphine-like opioid agonists in humans are unclear. In animals, relatively specific δ agonists produce analgesia and positive reinforcing effects at supraspinal sites and antinociception for thermal stimuli at spinal sites (6).

The novel opioid-like orphan receptor is coded by a gene (LC132, ORL1, XOR, ROR-6, or KOR3) that was originally identified because of its extensive nucleotide sequence homology with the δ receptor (7). The natural ligand for this receptor, an endogenous peptide (orphanin FQ/nociceptin (ORQ/N)) has been identified as a part of a larger protein (preoORQ/N), whose gene maps to human chromosome 8p21 (7).

Opioid receptors have seven transmembrane- spanning domains and three extra- and three intracellular loops. They couple to a pertussis toxin-sensitive G protein (G/G₀) to influence one or more second messenger pathways: cytoplasmic free Ca²⁺ [Ca²⁺]_I, the phosphatidylinositol-[Ca²⁺]_I system and the cyclic nucleotide cAMP (5, 6).

Opioids are primarily inhibitory. They close N-type voltage-operated calcium channels and open calcium-dependent inwardly rectifying potassium channels, resulting in hyperpolarization and reduced neuronal excitability. κ receptors may act only on calcium channels. P/Q-type Ca²⁺ channels may be inhibited by μ, but not by δ-receptor opioids. Opioids inhibit adenylyl cyclase, decreasing cAMP concentration. cAMP modulates neurotransmitter release (e.g. substance P) and activates and regulates protein kinase C. This alters the expression of intermediate early genes such as c-fos, a marker of activity in neurones that is associated with nociception and whose expression is depressed by morphine (5, 6).

Opioids also have excitatory effects that involve both disinhibition of interneurones and direct excitation of neurones themselves (5). At very low concentrations, acting through G_s proteins, they selectively stimulate neuronal adenylyl cyclase activity. This can produce transient increases in [Ca²⁺]_I, secondary to Ca²⁺ influx via L-type Ca²⁺ channel opening as well as mobilization of Ca²⁺ from inositol triphosphate (ITP)-sensitive intracellular stores (13). μ agonists may also stimulate Ca²⁺ entry into neurones via G protein-coupled activation of phospholipase C to increase ITP. Changes in [Ca²⁺]_I may contribute to opioid-induced inhibition of the release of neurotransmitters SP and glutamate from central and peripheral endings of primary afferents responsible for modulation of nociception (6). Calcium channel antagonists enhance morphine analgesia (14).

The OFQ/N receptor activates K⁺ conductance and modulates a variety of voltage-dependent Ca²⁺ currents: it inhibits N-type Ca²⁺ channels and modulates L-, N- and P/Q-types of voltage-gated Ca²⁺ channels. The OFQ/N receptor shares with the classic μ-, δ-, and κ-opioid receptors coupling to N-type Ca²⁺ channels and inwardly rectifying K⁺ channels. OFQ/N inhibits all neurones tested in the ventromedial raphe (including serotonergic neurones), and blocks antinociceptive neuronal activation responsible for the analgesic action of opioids in this region (7).

Opioid-induced analgesia

Opioid-induced analgesia occurs at multiple spinal and supraspinal sites (2, 4). μ-opioid agonists selectively inhibit nociceptive reflexes and induce profound analgesia when administered intrathecally or instilled locally into the dorsal horn of the spinal cord; other sensory modalities usually are unaffected (2, 4). Opioids modulate sensation carried by slowly conducting, unmyelinated C fibres in the dorsal horn. Pain transmission involves the release of SP, NKA, and glutamate. Release of these transmitters is inhibited by presynaptic activation of μ, δ, and κ receptors. Opioids also directly hyperpolarize and inhibit post-synaptic dorsal horn and nucleus caudalis neurones, decreasing the output of the spino- and quintothalamic tract neurones that convey nociceptive information to higher brain centres (6). Opioids interfere with the peripheral action of prostaglandins and inhibit neurogenic inflammation in the Moskowitz model of dural inflammation (15). All three classic opioid receptor subtypes occur on peripheral nerve endings. They are up-regulated during inflammation, and immune cells in peripheral tissue express opioid peptides (16).

Supraspinal opioid receptor activation results in the enhancement of descending inhibitory pathways (4). The periaqueductal grey may be a major site of the supraspinal component of analgesia. Profound analgesia can be produced by the instillation of morphine or electrical stimulation of the third ventricle or various sites in the midbrain and medulla. Electrical stimulation-induced analgesia is antagonized by naloxone, which suggests involvement of endogenous opioids. δ-opioid receptor analgesia is mediated spinally through the dorsal horn. δ agonists are also analgesic supraspinally in animal models at unknown sites. Animal models suggest that κ₁ receptor agonists mediate analgesia spinally, while at κ₃ receptor agonists act supraspinally (4, 8).

Simultaneous administration of morphine at both spinal and supraspinal sites results in a synergistic analgesic response, with a 10-fold reduction in the total dose of morphine necessary to produce equivalent analgesia at either site alone (17). In addition to the well-described spinal/supraspinal synergy, synergistic μ/μ– and μ/δ–receptor interactions also have been observed within the brainstem between the periaqueductal grey, locus ceruleus, and nucleus raphe magnus (18).

Opioid types

The opioids have been divided into three groups: morphine and related opioid agonists; opioids with mixed actions, such as nalorphine and pentazocine, which are agonists at some receptors and antagonists or very weak partial agonists at others; and opioid antagonists, such as naloxone. Mixed agonist/antagonists, such as pentazocine and nalorphine, can produce disturbing psychotomimetic effects that are not effectively blocked by naloxone (4, 8).

Although there are many compounds that have pharmacologic properties similar to morphine, none is clinically superior in relieving pain. Morphine-like drugs produce analgesia without loss of consciousness, and often without drowsiness, changes in mood, or mental clouding. Some patients experience euphoria. Pain relief by morphine-like opioids is relatively selective, without involvement of other sensory modalities. Mixed agonist/antagonists and partial agonists differ from morphine in that they are not full agonists at all opioid receptor subtypes. Nalorphine, cyclazocine, and nalbuphine are competitive μ antagonists but κ receptor agonists. Pentazocine and butorphanol are weaker μ antagonists or partial μ agonist and κ receptor agonists. The combination of μ antagonism coupled with κ agonism is responsible for the designation of these drugs as mixed agonist/antagonist agents (4, 8).

Clinical studies in migraine and tension-type headache

Duke University and the American Academy of Neurology, under contract to the Agency for Healthcare Research and Quality (AHRQ, formerly Agency for Healthcare Policy and Research (AHCPR)), identified and summarized evidence from controlled trials on the efficacy and tolerability of drug treatments for acute migraine headache (19, 20). The use of opioids is a subset of that analysis.

The results and methods have been published elsewhere (19, 20). The following is a brief summary. Trials were sought with a search strategy that combined the MeSH (medical subject heading) term ‘headache’ (exploded) and a previously published strategy for identifying randomized controlled trials in the January 1966 to December 1996 MEDLINE database. Other computerized bibliographic databases, textbooks, and experts were also utilized. Selection criteria included all English-language controlled trials involving patients with acute migraine headache in which at least one treatment offered was a drug treatment.

Data collection and analysis were based on the number of patients who obtained headache relief according to an a priori definition of at least a 50% reduction in pain severity. Results were recorded and used to calculate odds ratios for headache relief. Measures of pain severity reported as group means (and standard deviations) were used to calculate standardized mean differences (or effect sizes). Where similar trials provided data, a meta-analysis of efficacy measures was performed. The identity and rates of adverse events were recorded and statistically compared.

This section details data on the efficacy of treating acute headache pain using opioids administered by oral, nasal, and parenteral routes.

Oral opioids

Codeine-containing combination agents have been studied in both migraine and tension-type headache. Among patients with migraine, seven placebo- controlled, randomized trials tested the efficacy of a variety of oral codeine-containing agents, including acetaminophen plus codeine and proprietary combinations of acetaminophen and codeine.

Two studies compared acetaminophen plus codeine with placebo (21, 22). The two trials used slightly different formulations (400 mg plus 25 mg (21) and 650 mg plus 16 mg (22)).

Boureau et al. (21) compared acetaminophen plus codeine with placebo. Two different 2-h pain outcomes for analysis were used to calculate an odds ratio of 2.3 (1.5–3.5) for ‘complete or almost complete’ relief at 2 h, which confirms the study's finding of a statistically significant difference in favour of acetaminophen plus codeine for this outcome. The 20% difference in response rate between the active drug and placebo suggests that the difference between the two treatments is also clinically significant. The comparison of patients experiencing complete relief at 2 h yielded an odds ratio of 1.8 (1–3.2), which is just statistically significant.

Gawel et al. (22) compared acetaminophen plus codeine with placebo for the treatment of several types of headache and reported only limited separate results for migraine patients. The most appropriate outcome was the sum of pain intensity differences (SPID) measured over 5 h. There was no significant difference between acetaminophen plus codeine and placebo as far as this outcome was concerned, but no SPID scores and no P-value for the comparison were reported.

Two studies included comparisons of combinations of acetaminophen plus codeine plus doxylamine succinate (Mersyndol®) with placebo (22, 23).

Gawel et al. (22) also compared acetaminophen plus codeine plus doxylamine succinate with placebo. There was no significant difference between acetaminophen plus codeine plus doxylamine succinate and placebo, using the SPID, measured over 5 h, as an outcome measure.

Somerville (23) reported the percentage of patients reporting ‘partial or complete’ headache relief. An odds ratio of 5.2 (0.99–27) for complete relief of headache was calculated, which is not statistically significant. The investigators' analysis, which may have been more powerful, found that Mersyndol® was statistically superior to placebo for this outcome (P < 0.05). The 22% difference in response rate is clinically significant.

Three studies compared acetaminophen plus codeine phosphate plus buclizine hydrochloride plus dioctyl sodium sulfosuccinate (Migraleve®) with placebo.

In a study by Adam, headache duration data showed an effect size of 0.41 (−0.07 to 0.89), which confirms the study's finding that there was no significant difference between Migraleve® and placebo (24).

In a study by Carasso & Yehuda, an odds ratio of 31 (5.6–171) was calculated for ‘complete or considerable’ relief of migraine symptoms. This confirms the study's finding that Migraleve® was statistically superior to placebo and, together with the 64% difference in response rates, suggests a very large clinical difference between the two treatments. However, these results may be prone to bias because the study was not double-blinded and did not describe dropouts from the trial (25).

For Uzogara et al. two pain outcomes were reported (mean headache severity and headache index), but no firm conclusions could be drawn about them. Mean headache severity was actually lower for attacks treated with placebo than for attacks treated with Migraleve® in periods one (4.271 vs. 4.714) and two (3.179 vs. 4.222). The treatment term in the investigators' anova analysis was significant for this outcome (P = 0.022), but a carry-over effect (treatment–period interaction) was present (P = 0.016), which made interpretation of the treatment effect difficult (26).

Opioids were compared with other agents in a number of trials. Boureau (21) compared acetaminophen plus codeine with aspirin. Two different 2-h pain outcomes were used for analysis, one given in categorical terms (proportion of patients with complete or almost complete relief) and the other a continuous measure (pain intensity difference on the visual analogue scale (VAS), from 0 to 2 h. An odds ratio of 0.90 (0.61–1.3) for ‘complete or almost complete’ relief was calculated at 2 h, which confirms the study's finding that there was no significant difference between the two treatments for this outcome. From the continuous data on pain intensity difference form 0 to 2 h, an effect size of −0.21 (−0.41 to −0.01) was calculated. This effect size confirms the study's finding that aspirin was significantly better than acetaminophen plus codeine at reducing pain intensity at 2 h; however, the magnitude of the effect is small. This study also reported the percentage of patients experiencing complete relief at 2 h. An odds ratio of 0.78 (0.48–1.3) confirmed the study's finding that there was no significant difference between the two treatments for this outcome.

Acetaminophen plus codeine was compared with Fioricet® for the treatment of tension-type headache in one trial (27). Investigators found significantly better complete relief with Fioricet® at 4 h, but no difference at 2 h. Complete relief of headache was observed in similar proportions of patients taking Fioricet® and acetaminophen plus codeine at 2 h (27% and 25%, respectively). At 4 h, 56% of patients treated with Fioricet® obtained complete relief, compared with 39% of patients taking acetaminophen plus codeine; this difference is statistically significant (odds ratio 2.0; 95% confidence interval (CI) 1.0–4.1).

The General Practitioner Research Group (28) compared Migraleve® with Migril® (ergotamine tartrate 2 mg plus cyclizine 50 mg plus caffeine 100 mg). Patients graded their headache severity at the end of each attack on a scale of 1 to 3, with 3 being the most severe grade. The severity scores for all attacks were then added. There was no significant difference between the two treatments.

Hakkarainen et al. compared the combination drug Doleron® (aspirin 350 mg plus dextropropoxyphene chloride 65 mg plus phenazone 150 mg plus [2-diaminoethyl] phentiazin carboxyl chloride 5 mg plus caffeine 50 mg) with aspirin 500 mg. The only efficacy outcome reported (in terms of rank sums) was complete relief within 30 min. The investigators' analysis showed that Doleron® was significantly better than aspirin at providing complete relief within 30 min (P < 0.01). An effect size or odds ratio for this outcome based on the data reported in the study could not be calculated (29).

Hakkarainen et al. compared the combination drug Doleron Novum® (aspirin 350 mg plus dextropropoxyphene napsylate 100 mg plus phenazone 150 mg) with aspirin 500 mg. The only efficacy outcome reported (in terms of rank sums) was complete relief within 30 min. The investigators' analysis showed that Doleron Novum® was significantly better than aspirin for this outcome (P < 0.01) (30).

Hakkarainen et al. compared the combination drug Doleron® with ergotamine tartrate 1 mg. The only efficacy outcome reported (in terms of rank sums) was complete relief within 30 min. The investigators' analysis showed that there was no significant difference between Doleron® and ergotamine for this outcome (no P-value reported). No data on nausea and vomiting were reported. ‘Gastric distress’ was reported as an adverse event in 9% (16/175) of attacks treated with Doleron® and in 43% (75/175) of attacks treated with ergotamine (29).

Hakkarainen et al. compared the combination drug Doleron Novum® with ergotamine tartrate 1 mg. The only efficacy outcome reported (in terms of rank sums) was complete relief within 30 min. The investigators' analysis showed that there was no significant difference between Doleron Novum® and ergotamine for this outcome (no P-value reported). The study did not provide the data needed to calculate an effect size or odds ratio for complete relief (30).

The literature review identified three placebo- controlled trials of Fiorinal with Codeine® which included primarily patients with tension-type headache (31–33). No placebo-controlled trials of these agents have been conducted among patients with migraine.

All three trials reported significantly better PID scores with Fiorinal with codeine® than with placebo at both 2 h and 4 h. Friedman et al. (1988) also reported that > 50% headache relief was experienced at 4 h by 82% of patients treated with Fiorinal with Codeine®, compared with 56% of patients treated with placebo, a difference that is statistically significant (odds ratio 3.7; 95% CI 1.3–10) (32).

Direct comparisons between Fiorinal with Codeine® and Fiorinal® (without codeine) were permitted by the three studies discussed above (31–33). Pain intensity difference scores were significantly better for the codeine-containing compound in two of the three studies at 2 h (31, 32), and in one of the three studies at 4 h (31). At 4 h, the remaining two studies (32, 33) showed statistical trends (0.05 < P < 0.10) toward better PID for Fiorinal with Codeine®.

The magnitude of the difference between the two interventions can be estimated by considering the data on headache relief reported by Friedman et al. (32) and the pre- and post-treatment pain intensity scores reported by Hwang et al. (33). Friedman et al. (32) reported that better than 50% headache relief was achieved at 4 h by 82% of patients taking Fiorinal with Codeine® and by 71% of patients taking Fiorinal® alone; the resulting odds ratio was 1.9 (95% CI 0.66–5.4), which is not statistically significant. Hwang et al. (33) reported that mean pain intensity decreased from 2.75 (pretreatment) to 1.25 (4 h) in patients using Fiorinal with Codeine® (a 55% reduction), and from 2.93 to 1.64 in patients using Fiorinal® alone (a 44% reduction). These data yielded a small effect size of 0.29 (95% CI −0.45 to 1.0), which is not statistically significant. Neither of these studies had sufficient statistical power to demonstrate differences of 10% in the reported outcomes.

A single trial compared Fiorinal with Codeine® vs. butorphanol nasal spray (Stadol®) (34). It was the only study of Fiorinal with Codeine® conducted among patients with migraine and the only trial to use the International Headache Society (IHS) diagnostic criteria. It was also the largest of all the clinical trials of opioid drugs for headache (n = 275).

At 2 h, investigators reported that butorphanol was significantly better than Fiorinal with Codeine® for mean headache relief scores and for the percentage of patients reporting headache relief (defined as a reduction in headache severity from moderate or severe to mild or none). There was no significant difference between the two interventions for mean PID scores at this time point. Headache relief was achieved at 2 h by 47% of patients treated with Fiorinal with Codeine® and by 60% of patients treated with butorphanol (odds ratio 0.58; 95% CI 0.36–0.93).

At 4 h there was still no significant difference between the two interventions for PID and no significant difference between them for mean headache relief or percentage of patients reporting headache relief. Pain intensity plotted over time showed that pain relief occurred more quickly with butorphanol than with Fiorinal with Codeine®, thus accounting for the significant differences at early time points.

Transnasal opioids

Butorphanol nasal spray was superior to placebo in two trials. In one of them (35) treatment was administered in a clinical setting; in the other (36) patients treated themselves at home. Both provided measures of headache at 2 h.

Diamond et al. compared butorphanol nasal spray (1 mg IN) to methadone (10 mg IM) and placebo in a double-blind trial of 96 out-patients in a headache clinic. Using PID, both active treatments were superior to placebo and butorphanol was superior to methadone. The data on the cumulative sum of pain relief scores (TOTPAR) at 2 h was analysed. For the comparison of butorphanol vs. placebo, the effect size was 0.62 (0.12–1.12), confirming the study's finding that butorphanol was statistically significantly better than placebo for this outcome. Both the TOTPAR scores and the effect size estimate suggest that the difference between the two treatments was also clinically significant and of a relatively large magnitude (35).

Hoffert et al. (36) in a double-blind, placebo- controlled, parallel group trial, compared butorphanol (1 mg IN) with placebo in migraine patients treated at home. At 2 h, 60% of patients using butorphanol, compared with 18% of patients using placebo, had relief. This study reported data on the percentage of patients whose headache pain was reduced from moderate or severe to slight or none within 2 h. From these data an odds ratio of 6.8 (3–15) was calculated, which confirms the study's finding that butorphanol is statistically significantly better than placebo at providing headache relief at 2 h. The 42% difference in response rates suggests that the difference is also clinically significant and large in magnitude.

This study also provided data on the percentage of patients whose headache pain was reduced from moderate or severe to none within 2 h. These data yielded an odds ratio of 3.7 (1.3–10). This odds ratio and the percentages on which it is based suggest that butorphanol is significantly better, both statistically and clinically, than placebo at providing complete relief of headache at 2 h.

Goldstein et al. (34) compared Fiorinal® with codeine (butalbital plus aspirin plus caffeine plus codeine) with butorphanol, administered as a nasal spray (Stadol NS). Butorphanol was superior in efficacy to Fiorinal® with codeine at 2 h, but differences between the two treatments were not significant at 4 h.

The orally administered opiate compounds were associated with only slightly higher rates of adverse events than was placebo, and were comparable to aspirin and better than ergotamine. The most commonly reported adverse events with the opiate analgesics were dizziness, fatigue, nausea, and drowsiness. Adverse events were much more frequently reported with intranasal butorphanol than with placebo or with oral opiate analgesics, and most frequently involved dizziness, nausea/vomiting, drowsiness, and confusion. Complaints of an unpleasant taste and nasal irritation were also common and were probably related to the intranasal route of administration.

Parenteral opioids

Parenteral opioid analgesics are frequently used for the treatment of acute migraine in the Emergency Department (ED). Opioid analgesics are associated with well-known side-effects that may affect the functional status of patients (e.g. drowsiness) and reduce the drugs' effectiveness for migraine (e.g. nausea). The AHRQ literature review identified 15 publications reporting on 12 separate controlled trials of opioid analgesics for the treatment of acute migraine.

Analyses included 11 published reports on 10 separate trials. The included studies reported on the safety and efficacy of the following agents or combinations of agents: butorphanol IM, two trials; meperidine (pethidine) IM, one trial; meperidine plus dimenhydrinate IV, one trial; meperidine (pethidine) plus dimenhydrinate IM, one trial; meperidine (pethidine) plus hydroxyzine IM, three trials; meperidine (pethidine) plus promethazine IM, two trials; and methadone IM, one trial. All 10 trials included patients with both types of migraine (with and without aura). Three studies cited the IHS diagnostic criteria for migraine.

Diamond et al. (35) compared methadone IM, administered as a single 10 mg injection, with placebo. The TOTPAR scores at 2 h were analysed. At 2 h, TOTPAR scores were 2.54 for methadone and 1.10 for placebo. Based on these numbers, an effect size was 0.36 (−0.13 to 0.85), which is not statistically significant; however, the authors' analysis of the primary data showed a statistically significant benefit of methadone over placebo (P = 0.05).

Elenbaas et al. (37) compared three single doses of butorphanol IM (1, 2, and 3 mg) in patients presenting to the ED. A parenteral anti-nauseant was permitted if vomiting persisted. Pain intensity and relief data were reported from immediately before treatment and 15, 30, 45 and 60 min. Headache relief was measured on a 100-mm visual analogue scale. Mean relief scores (± sd) at 60 min were 40.6 (± 32.1), 75.5 (± 32.5), and 78.5 (± 35.2) in the 1, 2, and 3 mg groups, respectively. There were significant differences among the three groups (P = 0.006), but no pairwise comparisons were reported. Effect sizes for the various dose comparisons were: 1.1 (0.36–1.8) for 3 mg vs. 1 mg; 1.1 (0.32–1.8) for 2 mg vs. 1 mg; and 0.09 (−0.57 to 0.74) for 3 mg vs. 2 mg. The 3-mg and 2-mg doses were significantly better than the 1-mg dose, but there was no significant difference between the two higher doses. However, because of the wide confidence intervals, these data are consistent with the 3-mg dose being better than the 2-mg dose to a clinically important degree.

Belgrade et al. (38) compared single doses of butorphanol 2 mg IM with meperidine 75 mg plus hydroxyzine 50 mg IM. Results were reported for 30 min only in a blinded study. Headache intensity was measured on a 0–100 scale. Significant differences (P = 0.008) in mean reduction in headache severity scores from 0 to 30 min were found among the three treatments studied (there was also a DHE plus metoclopramide arm). On the basis of the continuous data, an effect size of 0.62 (−0.27 to 1.5) compared butorphanol with meperidine plus hydroxyzine. This effect size is not statistically significant.

The investigators also reported the percentage of patients in each treatment group with a > 90% reduction in headache severity from 0 to 30 min. Three of 19 patients in the butorphanol group (16%) and 0/22 patients in the meperidine plus hydroxyzine group (0%) reported this level of relief, yielding an odds ratio of 30 (0.31–2774), which is not statistically significant.

Diamond et al. (35) compared a single 10 mg injection of methadone IM with butorphanol IN administered initially in a 1-mg dose followed by a second dose at 1 h. At 2 h, TOTPAR scores were 2.54 for methadone and 3.57 for butorphanol. A not statistically significant effect size of −0.26 (−0.75 to 0.23) was calculated. The investigators' more powerful analysis found that the difference was statistically significant in favour of butorphanol (P < 0.05). Any difference between the two treatments is not likely to have been clinically significant.

Two trials compared meperidine plus dimenhydrinate IV with different antinauseants (39, 40).

Lane et al. (39) compared meperidine 0.4 mg/kg, repeated at 15-min intervals up to a maximum of three doses, plus dimenhydrinate IV with chlorpromazine IV 0.1 mg/kg, repeated at 15-min intervals up to a maximum of three doses. Dimenhydrinate 25 mg was administered along with only the first dose of meperidine. Pain intensity was evaluated on 10 cm visual analogue scale.

The primary outcome reported by the investigators was the change in mean pain intensity scores from time zero to a final time point, defined as 45 min for those patients who required rescue medication or the time of discharge in those who did not require rescue medication. Mean change scores were −4.45 (± 2.62) for the meperidine plus dimenhydrinate group and −7.06 (± 2.18) for the chlorpromazine group. An effect size of −1.1 (−1.7 to −0.49) was calculated, which supports the study's finding that chlorpromazine was significantly better than meperidine plus dimenhydrinate (P < 0.001).

Stiell et al. (40) compared intramuscular meperidine plus dimenhydrinate with methotrimeprazine. Patients received a single dose of either meperidine 75 mg plus dimenhydrinate 50 mg or methotrimeprazine 37.5 mg. Patients measured headache relief at 1 h on a 10-cm visual analogue scale. Mean pain relief scores for the meperidine plus dimenhydrinate and methotrimeprazine groups were 6.63 (± 3.43) and 5.84 (± 2.90), respectively. The effect size corresponding to these figures was 0.25 (−0.21 to 0.71), which confirms the study's finding that the difference between the two groups for this outcome was not statistically significant (P = 0.29).

Three trials compared meperidine with or without an antinauseant with the non-steroidal anti-inflammatory drug (NSAID), ketorolac (41–43).

Larkin & Prescott (43) compared a single dose of intramuscular meperidine 75 mg with ketorolac 30 mg. Pain relief was measured on a verbal analogue scale that ranged from ‘no relief’ to ‘complete relief.’ Meperidine was significantly better than ketorolac at providing headache relief at 1 h (P = 0.02, Wilcoxon rank sum test). An odds ratio for this outcome could not be calculated.

Duarte et al. (42) compared single doses of meperidine (100 mg) plus hydroxyzine (50 mg IM) with ketorolac (60 mg IM). Both continuous data on headache intensity and dichotomous data on headache relief were analysed. Headache pain intensity was graded before treatment and again at 60 min on a visual analogue scale of 0–10. Pretreatment mean headache intensity scores were 8.28 (± 1.65) for the meperidine plus hydroxyzine group and 7.74 (± 1.84) for the ketorolac group (no P-value reported). At 60 min, mean scores were 3.37 (± 3.40) and 3.35 (± 2.92), respectively (P = 0.76). A statistically significant effect size for the change in headache intensity from 0 to 60 min of 0.006 (−0.55 to 0.56) was calculated.

Headache relief was measured on a five-point scale. A score of ‘complete relief’ or ‘great deal of relief’ was considered a treatment success. At 60 min, this level of relief had been achieved in 14/25 (56%) cases treated with meperidine plus hydroxyzine and 15/25 (60%) cases treated with ketorolac, generating an odds ratio of 0.85 (0.28–2.6), which supports the study's finding that there was no significant difference between the two interventions for this outcome (P = 0.77).

Davis et al. (41) compared a single dose of meperidine 75 mg plus promethazine 25 mg IM with ketorolac 60 mg IM. Headache relief was defined as a reduction of four or more units on a scale of 0–10. At 1 h, 14/22 (64%) patients receiving meperidine plus promethazine reported relief, compared with 10/20 (50%) patients in the ketorolac group. The odds ratio corresponding to these figures is 1.7 (0.51–6), which confirms the study's finding that there was no significant difference between the two interventions for this outcome (P = 0.372).

The odds ratios from the three trials described above (41) were combined to get a summary odds ratio of 1.7 (0.35–8) for the 1-h pain relief outcomes measured in these trials. This summary odds ratio is statistically insignificant, but does not rule out the possibility of a clinically significant difference between the two drugs.

Belgrade et al. (38) compared single doses of butorphanol 2 mg IM with DHE 1 mg plus metoclopramide 10 mg IV. Headache pain was measured before and after treatment on a scale of 0–100. The primary efficacy outcome was the mean reduction in headache severity scores from 0 to 30 min. An effect size of −0.14 (−0.76 to 0.48) comparing butorphanol with DHE plus metoclopramide for this outcome was calculated, which is not statistically significant.

Three of 19 (16%) patients treated with butorphanol and 8/21 (38%) treated with DHE plus metoclopramide achieved a > 90% reduction in headache severity from 0 to 30 min. These numbers yielded statistically significant odds ratio of 0.30 (0.67–1.4) in favour of DHE plus metoclopramide.

Belgrade et al. (38) compared single doses of meperidine 75 mg plus hydroxyzine 50 mg IM and dihydroergotamine (DHE) 1 mg plus metoclopramide 10 mg IV. Results were reported for 30 min only.

Headache pain intensity was measured before and after treatment on a 0–100 scale. The primary efficacy outcome reported was the mean reduction in headache severity scores from 0 to 30 min. A statistically significant effect size of −0.76 (−1.4 to −0.12) was calculated in favour of DHE plus metoclopramide. The fairly large effect size suggests that the difference between the two treatments was also clinically significant. The investigators also reported the percentage of patients in each treatment group with a > 90% reduction in headache severity from 0 to 30 min. A statistically significant odds ratio was calculated in favour of DHE plus metoclopramide of 0.010 (< 0.001–0.91).

Klapper & Stanton (44) compared the same drugs as Belgrade et al. (38) but used a higher dose of hydroxyzine (75 mg vs. 50 mg). Headache severity was graded on a scale of 0–3 (none, mild, moderate, or severe). All patients' headaches were moderate or severe (grade 2 or 3) before treatment. Both treatment groups experienced significant improvement in mean headache severity scores from 0 to 60 min. An effect size of −1.02 (−1.8 to −0.23) was calculated, which confirms the study's finding that DHE plus metoclopramide was significantly more effective than meperidine plus hydroxyzine at reducing headache pain (P = 0.006). The difference was clinically significant as well.

Scherl & Wilson (45) compared meperidine (75 mg with promethazine 25 mg) with DHE (0.5 mg), only half the dose used in the preceding two trials; metoclopramide 10 mg was given along with the DHE. Pain relief was measured at 60 min on a Likert-type scale of 0–5, where 1 equals 100% relief and 5 equals no relief. The mean percent of pain relief for each group was reported (77.2% for meperidine plus promethazine vs. 86.2% for DHE plus metoclopramide). A not statistically significant effect size of −0.13 (−0.88 to 0.63) was calculated.

Adverse events were similar for all the parenterally administered opioid analgesics, and included sedation, nausea, and dizziness.

Summary of clinical trials (Table 3)

The available clinical trials that examine opioid drug use support the intolerability and effectiveness in relieving of head pain in the episodic treatment of acute migraine and tension-type headache.

TABLE 3

Clinical trials of opioids

Drug	Population	Findings
APAP/Codeine	Migraine	Better for HA relief than placebo (2 of 3 trials)
	Migraine	No better than aspirin (1 trial)
	Tension-type	No better complete relief than Fioricet® @ 2 h (1 trial)
	Tension-type	Less complete relief than Fioricet® @ 4 h (1 trial)
APAP/codeine/doxylamine	Migraine	No better (HA complete relief, SPID) than placebo (2 of 2 trials)
APAP/codeine/doxylamine	Migraine	No better SPID than APAP/codeine (1 trial)
APAP/codeine/buclizine	Migraine	Better HA relief than placebo (1 of 3 trials)
APAP/codeine/buclizine	Migraine	No better for HA severity than ergotamine/cyclizine/caffeine (Migril®)
Butorphanol (IM)	Migraine	No better for HA relief than meperidine/hydroxyzine (IM) (1 trial)
Butorphanol (IM)	Migraine	No better for HA relief than dihydroergotamine/metoclopramide (IV) (1 trial)
Butorphanol (IN)	Migraine	Better for HA severity than placebo (2 of 2 trials)
Butorphanol (IN)	Doleron®	Migraine	Better for HA relief than aspirin (1 of 1 trial)
No better for HA relief than ergotamine tartrate	Doleron®	Migraine
Doleron novum®	Migraine	Better for HA relief than aspirin (1 of 1 trial)
Doleron novum®	Migraine	No better for HA relief than ergotamine tartrate
Fiorinal® with Codeine	Tension-type	Better for PID than placebo (3 of 3 trials)
	Tension-type	Better for PID than Fiorinal® (1 of 3 trials)
	Less HA relief than butorphanol (1 trial)
Meperidine (IV)	Migraine	No better than ketorolac (IM) (1 trial)
Meperidine/promethazine (IV)	Migraine	No better than placebo (1 trial)
		No better than ketorolac (IM) (2 of 2 trials)
		No better for HA relief than dihydroergotamine/metoclopramide (IV) (1 trial)
Meperidine/dimenhydrinate (IV)		Migraine	Less reduction in HA severity than chlorpromazine (IV) (1 trial)
Meperidine/dimenhydrinate (IV)	No better for HA severity than methotrimeprazine (IV) (1 trial)	Migraine
Meperidine/hydroxyzine IM	Migraine	No better HA relief than butorphanol (IM)
Meperidine/hydroxyzine IM	Migraine	Less HA relief than dihydroergotamine/metoclopramide (IV) (2 trials)
No better HA relief than ketorolac (IM) (1 trial)

The evidence for their use falls short of what is needed for clinical practice in several respects. First, the available trials do not address one role in which opioid drugs are often used, that is as rescue medications after other treatments have failed. Second, by focusing on short-term pain relief of acute headache attacks, these studies do not address clinically important questions about frequent or prolonged use of opioid analgesics, such as rebound headache, tolerance, and dependence.

Headache treatment with opioids

The pharmacologic treatment of headache can be acute or preventive. Acute treatment attempts to abort (reverse or stop the progression of) a headache after it has started. Acute treatment can be non-specific (for any pain disorder) or specific (for only headache). Non-specific medications include analgesics, NSAIDs, corticosteroids, neuroleptics, and opioids. Specific medications include the ergots and triptans. Ergotamine, DHE, and the triptans are effective first-line drugs for the treatment of migraine and can and should be used if there are no contraindications. These drugs cannot be used in the presence of pregnancy, uncontrolled hypertension, or coronary, cerebral or peripheral vascular disease.

The choice of acute medication depends on headache frequency and severity, the time to peak onset of pain, the presence of associated symptoms, the presence of coexistent illnesses, and the patient's treatment response profile. Many patients find relief with simple analgesics or NSAIDs. Analgesics are frequently combined with caffeine and/or butalbital in an attempt to enhance their effectiveness. They are also combined with less potent opioids such as codeine. In the USA, codeine or codeine combinations were used in a third of physicians' prescriptions for chronic or severe pain (46). In Norway, 28% of women and 13% of men used analgesics in the previous 2 weeks, most often for headache (46). No matter what acute headache drug is used, the amount should be limited to prevent overuse.

Opioids may be considered for patients who have infrequent, moderate-to-severe headaches that do not respond to standard medication. Opioids may also be considered in patients who cannot use specific headache medications because of coexisting disease or the lack of a diagnosis (such as the patient presenting to the ED with a new headache). They are one of the safest treatments for the pregnant patient when given in limited amounts. They are useful for severe middle-of-the-night headache and as a rescue medication. A self-administered rescue medication should be prescribed for severe migraine, since most treatments do not always work. In fact, the triptans may not work at all in as many as 20–30% of attacks. While rescue medications often do not maintain normal function, they permit the patient to achieve relief of pain and suffering without the discomfort and expense of a visit to the physician's office or ED. Rescue medications include opioids and neuroleptics.

Opioids can be used in patients who have not overused or abused medication or violated treatment recommendations. They should be avoided or used cautiously and restrictively in patients who have demonstrated addictive tendencies or have a family history of addictive disease. To avoid the risk of excessive use in treatment-resistant patients, strict limits should be set and small amounts of medication prescribed (47). The limits can be relaxed in women who are menstruating or pregnant. Meperidine, for example, is often useful in the pregnant patient, and occasional opioid use is appropriate for patients who cannot tolerate or do not respond to ergots, triptans, or other symptomatic medications.

Opioid dosages should be adjusted to account for the difference in bioavailability between the oral, parenteral, and rectal routes of administration (Table 2). The selection of a specific drug should be based on its route of administration, adverse effect profile, time to peak drug levels, and bioavailability. A non-oral route should be considered when there is severe nausea or vomiting. The agonist-antagonist opioids such as butorphanol and nalbuphine have lower abuse potential than the pure agonists. Parenteral butorphanol (2–3 mg) produces analgesia and respiratory depression equal to that of 10 mg of morphine (with similar onset, peak, and duration of action) or 80 mg of meperidine. Butorphanol's plasma half-life is about 3 h; higher values are observed in the elderly. Like other κ receptor agonists, there is much less of an increase in respiratory depression with higher doses compared with morphine and other μ-receptor agonists.

TABLE 2

Doses of opioids equivalent to 10 mg parenteral morphine

Drug	Oral dose (mg)	Oral-to-parenteral dose ratio	Parenteral dose (mg)
Butorphanol	NA	NA	2
Codeine	200	1.5:1	130
Hydromorphone	7.5	5:1	1.5
Meperidine	300	4:1	75
Methadone	20	2:1	10
Morphine
Single dose	60	6:1	10
Repeated dose	30	3:1	10
Oxycodone	15	2:1	30

Opioids should be limited to one or two doses a week. Although admittedly controversial, some pain authorities have argued that the liberal use of opioids in intractable headache (e.g. intractable menstrual migraine) or special circumstances (e.g. elderly patients in whom the otherwise standard treatment of ergotamine is contraindicated) is justifiable.

Based on the evidence reports the following recommendations can be made. Opioids (nasal): butorphanol is a treatment option for migraine and headache patients when other medications cannot be used or for use as a rescue medication when significant sedation would not jeopardize the patient. As with all opioids and most acute headache treatments, overuse and dependency potential limit the usefulness of butorphanol for acute migraine treatment.

The major side-effects of butorphanol are drowsiness, weakness, sweating, feelings of floating, and nausea. The incidence of psychotomimetic side-effects is lower than equianalgesic doses of pentazocine, but it is qualitatively similar.

Oral opioid combinations (e.g. aspirin or acetaminophen plus codeine) may be considered for use in acute migraine when sedation side-effects will not put the patient at risk and/or the risk of abuse has been addressed.

Parenteral opioids may be considered for rescue therapy in a supervised setting for acute migraine when sedation side-effects will not put the patient at risk and/or the risk of abuse has been addressed.

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