Spontaneous Opioid Withdrawal Research Articles

Biological sex influences sleep phenotype in mice experiencing spontaneous opioid withdrawal.

Aversive symptoms, including insomnia experienced during opioid withdrawal, are a major drive to relapse; however, withdrawal-associated sleep symptomatology has been little explored in preclinical models. We describe here a model of opioid withdrawal in mice that resembles the sleep phenotype characteristic of withdrawal in humans. Male and female C57BL/6 mice were instrumented with telemeters to record electroencephalogram, electromyogram, activity and subcutaneous temperature. All mice received two treatments separated by a 16-day washout period: (1) saline (volume: 10 ml kg-1); or (2) ascending doses of morphine (5, 10, 20, 40 and 80 mg kg-1; volume: 10 ml kg-1) for 5 days at Zeitgeber time 1 and Zeitgeber time 13. Recordings for the first 71 hr after treatment discontinuation (withdrawal days 1-3) and for 24 hr on withdrawal days 5 and 7 were scored for sleep/wake state, and sleep architecture and electroencephalogram spectral data were analysed. Morphine was acutely wake- and activity-promoting, and non-rapid eye movement and rapid eye movement sleep were increased during the dark phase on withdrawal day 2 in both sexes. While non-rapid eye movement delta power (0.5-4.0 Hz), a measure of sleep intensity, was reduced during the light phase on withdrawal day 1 and the dark phase on withdrawal day 2 in both sexes, female mice also exhibited changes in the duration and the number of bouts of sleep/wake states. These observations of fragmented sleep on withdrawal days 1-3 suggest poorer sleep consolidation and a more pronounced withdrawal-associated sleep phenotype in female than in male mice. These data may indicate a greater sensitivity to morphine, a more distinct aversive sleep phenotype and/or a faster escalation to dependence in female mice.

Modeling spontaneous opioid withdrawal in male and female outbred mice using traditional endpoints and hyperalgesia.

Opioid withdrawal significantly impacts drug dependence cycles as hyperalgesia associated with withdrawal is often a reason for continued drug use. Animal models of addiction are important tools for studying how drug dependence and withdrawal impact not only normal neurocircuitry but also the effectiveness of potential treatments for dependence and withdrawal. We conducted a study of the time course of spontaneous morphine withdrawal in outbred male and female mice that can be used to examine sex differences in male and female mice using both traditional somatic endpoints and mechanical hyperalgesia as an endpoint of withdrawal. Male and female national institute of health (NIH) Swiss mice were made dependent upon morphine using an escalating dosing schedule. Injections were stopped after 5 days. Withdrawal behavior was assessed at time intervals up to 106 h after the final injection. Numbers of forepaw tremors, wet-dog shakes, jumps and other behaviors were scored to create a global score. Paw pressure readings were then also taken to track changes in sensitivity to a painful stimulus over time. Male and female mice had approximately similar withdrawal severity peaking at 24 h after the final injection as measured by composite global scores. Females did exhibit an earlier and greater frequency of tremors than males. Although males and females showed similar hyperalgesia during withdrawal, females recovered faster. Spontaneous opioid withdrawal peaking at 24 h was demonstrated in male and female NIH Swiss mice. We also successfully demonstrated that hyperalgesia is an endpoint that varies over the course of withdrawal.

Anterior cingulate cortex and its projections to the ventral tegmental area regulate opioid withdrawal, the formation of opioid context associations and context-induced drug seeking.

Clinical evidence suggests that there are correlations between activity within the anterior cingulate cortex (ACC) following re-exposure to drug-associated contexts and drug craving. However, there are limited data contributing to our understanding of ACC function at the cellular level during re-exposure to drug-context associations as well as whether the ACC is directly related to context-induced drug seeking. Here, we addressed this issue by employing our novel behavioral procedure capable of measuring the formation of drug-context associations as well as context-induced drug-seeking behavior in male mice (8–12 weeks of age) that orally self-administered oxycodone. We found that mice escalated oxycodone intake during the long-access training sessions and that conditioning with oxycodone was sufficient to evoke conditioned place preference (CPP) and drug-seeking behaviors. Additionally, we found that thick-tufted, but not thin-tufted pyramidal neurons (PyNs) in the ACC as well as ventral tegmental area (VTA)-projecting ACC neurons had increased intrinsic membrane excitability in mice that self-administered oxycodone compared to controls. Moreover, we found that global inhibition of the ACC or inhibition of VTA-projecting ACC neurons was sufficient to significantly reduce oxycodone-induced CPP, drug seeking, and spontaneous opioid withdrawal. These results demonstrate a direct role of ACC activity in mediating context-induced opioid seeking among other behaviors, including withdrawal, that are associated with the DSM-V criteria of opioid use disorder.

Anterior cingulate cortex is necessary for spontaneous opioid withdrawal and withdrawal-induced hyperalgesia in male mice.

The anterior cingulate cortex (ACC) is implicated in many pathologies, including depression, anxiety, substance-use disorders, and pain. There is also evidence from brain imaging that the ACC is hyperactive during periods of opioid withdrawal. However, there are limited data contributing to our understanding of ACC function at the cellular level during opioid withdrawal. Here, we address this issue by performing ex vivo electrophysiological analysis of thick-tufted, putative dopamine D2 receptor expressing, layerV pyramidal neurons in the ACC (ACC L5 PyNs) in a mouse model of spontaneous opioid withdrawal. We found that escalating doses of morphine (20, 40, 60, 80, and 100 mg/kg, i.p. on days 1-5, respectively) injected twice daily into male C57BL/6 mice evoked withdrawal behaviors and an associated withdrawal-induced mechanical hypersensitivity. Brain slices prepared 24 h following the last morphine injection showed increases in ACC L5 thick-tufted PyN-intrinsic membrane excitability, increases in membrane resistance, reductions in the rheobase, and reductions in HCN channel-mediated currents (IH). We did not observe changes in intrinsic or synaptic properties on thin-tufted, dopamine D1-receptor-expressing ACC L5 PyNs recorded from male Drd1a-tdTomato transgenic mice. In addition, we found that chemogenetic inhibition of the ACC blocked opioid-induced withdrawal and withdrawal-induced mechanical hypersensitivity. These results demonstrate that spontaneous opioid withdrawal alters neuronal properties within the ACC and that ACC activity is necessary to control behaviors associated with opioid withdrawal and withdrawal-induced mechanical hypersensitivity. The ability of the ACC to regulate both withdrawal behaviors and withdrawal-induced mechanical hypersensitivity suggests overlapping mechanisms between two seemingly distinguishable behaviors. This commonality potentially suggests that the ACC is a locus for multiple withdrawal symptoms.

Comparative benefits of social housing and buprenorphine on wheel running depressed by morphine withdrawal in rats.

Social support and opioid replacement therapy are commonly used to treat opioid withdrawal. The present study tested the hypothesis that social housing and buprenorphine administration can restore wheel running depressed by morphine withdrawal in rats. Experiment 1 assessed disruptive side effects of buprenorphine and found that administration of low doses (3.2, 10, & 32µg/kg, s.c.) had no impact on voluntary wheel running. Experiment 2 assessed the impact of social housing and acute buprenorphine administration (10µg/kg) on morphine withdrawal. Two 75mg morphine pellets were implanted for 3days to induce dependence. Removal of the morphine pellets caused a decrease in body weight, increase in wet dog shakes, and depression of wheel running during the normally active dark phase of the circadian cycle. Social housing restored wheel running and reduced the number of wet dog shakes but did not affect body weight. Administration of buprenorphine restored wheel running depressed by morphine withdrawal for 2days in individually housed rats and produced time-dependent changes in socially housed rats: Depression of wheel running in the 3h following administration and restoration of running subsequently compared to saline-treated controls. The impact of buprenorphine and social housing to reduce the effect of morphine withdrawal in rats is consistent with the use of opioid substitution therapy and psychotherapy/social support to treat opioid withdrawal in humans. These data provide further validation for the clinical relevance for the use of wheel running to assess spontaneous opioid withdrawal.

Use of home cage wheel running to assess the behavioural effects of administering a mu/delta opioid receptor heterodimer antagonist for spontaneous morphine withdrawal in the rat

Opioid abuse is a major health problem. The objective of the present study was to evaluate the potentially disruptive side effects and therapeutic potential of a novel antagonist (D24M) of the mu-/delta-opioid receptor (MOR/DOR) heterodimer in male rats. Administration of high doses of D24M (1 & 10 nmol) into the lateral ventricle did not disrupt home cage wheel running. Repeated twice daily administration of increasing doses of morphine (5–20 mg/kg) over 5 days depressed wheel running and induced antinociceptive tolerance measured with the hot plate test. Administration of D24M had no effect on morphine tolerance, but tended to prolong morphine antinociception in non-tolerant rats. Spontaneous morphine withdrawal was evident as a decrease in body weight, a reduction in wheel running and an increase in sleep during the normally active dark phase of the circadian cycle, and an increase in wheel running and wakefulness in the normally inactive light phase. Administration of D24M during the dark phase on the third day of withdrawal had no effect on wheel running. These data provide additional evidence for the clinical relevance of home cage wheel running as a method to assess spontaneous opioid withdrawal in rats. These data also demonstrate that blocking the MOR/DOR heterodimer does not produce disruptive side effects or block the antinociceptive effects of morphine. Although administration of D24M had no effect on morphine withdrawal, additional studies are needed to evaluate withdrawal to continuous morphine administration and other opioids in rats with persistent pain.

Establishing a time course for spontaneous opioid withdrawal in male and female outbred mice using an abbreviated dependence paradigm

Opioid withdrawal is often a limiting factor in recovery from opioid dependence due to negative reinforcement caused by continued use of opioids in order to avoid the distressing withdrawal symptoms. In animal models of dependence, opioid withdrawal is frequently precipitated using opioid antagonists and the severity of withdrawal is related to the level of dependence. However, this model lacks face validity when investigating new treatment possibilities for opioid withdrawal because most human addicts are not exposed to an antagonist in order to precipitate withdrawal. Furthermore, results from animal experiments suggest that spontaneous and precipitated withdrawal involve different mechanisms and may favor different symptoms of withdrawal. These experiments were conducted to investigate the timeline of spontaneous withdrawal in an outbred mouse model using an abbreviated dependence paradigm. Male and female NIH Swiss mice were injected with escalating doses of morphine twice daily (50–125 mg/kg morphine) over a period of four days. On the fifth day, mice were given a final dose of morphine and withdrawal symptoms were assessed at 5, 10, 24, 34, 48, 58, 72, 82, 96, and 106 hrs after the final injection. Withdrawal symptoms were assessed by global scores for an overall picture and by counting the number of tremors, wet dog shakes, and jumps. Results showed a robust withdrawal time course that peaked at 24 hrs in both sexes as assessed by global score. When broken down, wet dog shakes and tremors proved to be the most reliable indicator of severity of withdrawal and females showed more tremors than males for the 1st 24 hours of the time course. These results establish a spontaneous withdrawal time course in an outbred strain of mouse that shows that dependence can be reliably established over a four‐day period using fairly high escalating doses of morphine. Furthermore, these results suggest that individual symptoms of withdrawal should be assessed over time as well as global score.Support or Funding InformationSupported in part by the State of Washington Initiative Measure No.171.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Sex Differences in Regional Brain Glucose Metabolism Following Opioid Withdrawal and Replacement.

Methadone and buprenorphine are currently the most common pharmacological treatments for opioid dependence. Interestingly, the clinical response to these drugs appears to be sex specific. That is, females exhibit superior therapeutic efficacy, defined as extended periods of abstinence and longer time to relapse, compared with males. However, the underlying metabolic effects of opioid withdrawal and replacement have not been examined. Therefore, using 18FDG and microPET, we measured differences in regional brain glucose metabolism in males and females following morphine withdrawal and subsequent methadone or buprenorphine replacement. In both males and females, spontaneous opioid withdrawal altered glucose metabolism in regions associated with reward and drug dependence. Specifically, metabolic increases in the thalamus, as well as metabolic decreases in insular cortex and the periaqueductal gray, were noted. However, compared with males, females exhibited increased metabolism in the preoptic area, primary motor cortex, and the amygdala, and decreased metabolism in the caudate/putamen and medial geniculate nucleus. Methadone and buprenorphine initially abolished these changes uniformly, but subsequently produced their own regional metabolic alterations that varied by treatment and sex. Compared with sex-matched control animals undergoing spontaneous opioid withdrawal, male animals treated with methadone exhibited increased caudate/putamen metabolism, whereas buprenorphine produced increased ventral striatum and motor cortex metabolism in females, and increased ventral striatum and somatosensory cortex metabolism in males. Notably, when treatment effects were compared between sexes, methadone-treated females showed increased cingulate cortex metabolism, whereas buprenorphine-treated females showed decreased metabolism in cingulate cortex and increased metabolism in the globus pallidus. Perhaps the initial similarities in males and females underlie early therapeutic efficacy, whereas these posttreatment sex differences contribute to clinical treatment failure more commonly experienced by the former.

Commentary on Nikoo et al. (2017): The role of research.

Opium tincture (OT) is used in Iran because it has two critical advantages—it is cheap, and it is less stigmatized than methadone. Stigma, and the problem of funding stigmatized treatments, is an issue in every country. Might OT be a solution? The evidence is limited, but reviewing it is useful. Nikoo and colleagues 1 report that in Iran there are 64 000 people in treatment with opium tincture (OT), the majority in slow withdrawal programmes. They have weighed the evidence concerning this preparation and found it wanting. They found observational trials of OT in substitution treatment, but no controlled trials. There were two controlled trials of OT in opioid withdrawal, with inconclusive results. Is OT a suitable medication for managing opioid dependence? Cost is one reason why the government of Iran used OT, and in low-income countries lower-cost treatment options are critical. Parsimony might seem a poor basis for choosing a medication without evidence to support it. However, absence of evidence of effectiveness is not evidence of absence of effectiveness. There are grounds for believing that almost any opioid can be used satisfactorily in substitution treatment 2. Well-controlled trials might reveal marginal differences in efficacy, but morphine, codeine and dihydrocodeine, to name a few opioids, have been used in observational studies 3, 4. OST medications do not even need to be long-acting or administered orally, as demonstrated by the effectiveness of injectable diamorphine and hydromorphone 5. Substitute medications work more effectively if they attenuate the effect of injected heroin—which is why high-dose methadone, inducing high opioid tolerance, is more effective than lower doses 6. As expected, a dose effect with OT was noted by Nikoo, with higher doses being more effective. In choosing between opioid drugs for substitution treatment, it might be a case of ‘anything goes’ (as long as given in sufficient dose); but in delivering medication to individuals, it is not the case that any approach is good enough. There are wide variations in how treatment is delivered 7—and better structured and supported treatment is more expensive to deliver and produces more effective outcomes 8. A more relevant question is whether slow opioid withdrawal a suitable treatment. Nikoo and colleagues comment that ‘we still do not have a satisfactory safe and effective treatment for detoxification and maintenance treatment of opioid dependence’; but spontaneous opioid withdrawal is not life-threatening. Most people dependent upon street opioids go through multiple episodes of withdrawal without formal treatment. On safety grounds, there is little need to offer detoxification—on the contrary, there is consistent evidence that post-detoxification heroin users are at increased risk of death 9. We can make withdrawal faster (rapid detoxification), or we can make it slower and less aversive, but however it is conducted relapse rates are high and risks of death post-withdrawal are increased 2, 10. The other major for using OT in Iran was the stigma against methadone. Stigma corrodes all aspects of substitution treatment. Stigma deters people from participating, and families pressure patients to avoid OST 11. People hate being on methadone, and drop out. Stigma against substitution treatment is one reason that professionals offer, and patients choose, detoxification rather than maintenance. The research reviewed by Nikoo and colleagues may permit few conclusions about OT relative to other medications, but it is important, none the less. Research helps to destigmatize treatment. It frames addiction as an empirical problem to be investigated, rather than an ethical problem to be corrected. It focuses not on the daily frustrations of dosing large numbers of people with minimal friction, but on the question of whether there are things we could do more effectively. It identifies end-points against which to evaluate treatment, guiding staff and patients towards realistic objectives and away from magical thinking. These ‘side effects’ of research into addiction are its greatest benefits—more valuable even than the occasional reporting of a vaguely relevant finding. Most of us have given up waiting for the big breakthrough that will cure addiction, but we still value the research enterprise. Research, even negative findings, helps us to think—and to cope with the stigma that bears down upon everyone involved in addiction. J.B. has received speaker's fees from Indivior and consultancy fees from Martindale Pharma.

A case of rhabdomyolysis associated with severe opioid withdrawal

While the risk of opioid overdose is widely accepted, the dangers of opioid withdrawal are far less clearly defined. The purpose of this publication is to provide evidence against the erroneous clinical dictum that opioid withdrawal is never life-threatening. This case report (N = 1) illustrates an unfortunate, common scenario of a man abusing prescription opioids and heroin. His attempt at self-detoxification with buprenorphine-naloxone resulted in life-threatening opioid withdrawal. A detailed account of each day of his withdrawal period was documented by patient and family report and review of all medical records. The patient was contacted three months after hospitalization to verify information and determine progress in treatment and abstinence from drugs and alcohol. A review of the literature was completed on severe cases of precipitated and spontaneous opioid withdrawal followed by a discussion of the significance as it relates to this case. Given the widespread use of prescription opioids and opioid maintenance treatment, physicians should be aware of the complications of acute opioid withdrawal and should be equipped to treat these complications.

A Double Blind, within Subject Comparison of Spontaneous Opioid Withdrawal from Buprenorphine versus Morphine

Preliminary evidence suggests that there is minimal withdrawal after the cessation of chronically administered buprenorphine and that opioid withdrawal symptoms are delayed compared with those of other opioids. The present study compared the time course and magnitude of buprenorphine withdrawal with a prototypical μ-opioid agonist, morphine. Healthy, out-of-treatment opioid-dependent residential volunteers (N = 7) were stabilized on either buprenorphine (32 mg/day i.m.) or morphine (120 mg/day i.m.) administered in four divided doses for 9 days. They then underwent an 18-day period of spontaneous withdrawal, during which four double-blind i.m. placebo injections were administered daily. Stabilization and spontaneous withdrawal were assessed for the second opioid using the same time course. Opioid withdrawal measures were collected eight times daily. Morphine withdrawal symptoms were significantly (P < 0.05) greater than those of buprenorphine withdrawal as measured by mean peak ratings of Clinical Opiate Withdrawal Scale (COWS), Subjective Opiate Withdrawal Scale (SOWS), all subscales of the Profile of Mood States (POMS), sick and pain (0-100) Visual Analog Scales, systolic and diastolic blood pressure, heart rate, respiratory rate, and pupil dilation. Peak ratings on COWS and SOWS occurred on day 2 of morphine withdrawal and were significantly greater than on day 2 of buprenorphine withdrawal. Subjective reports of morphine withdrawal resolved on average by day 7. There was minimal evidence of buprenorphine withdrawal on any measure. In conclusion, spontaneous withdrawal from high-dose buprenorphine appears subjectively and objectively milder compared with that of morphine for at least 18 days after drug cessation.

L-theanine attenuates abstinence signs in morphine-dependent rhesus monkeys and elicits anxiolytic-like activity in mice

l-theanine, 2-amino-4-(ethylcarbamoyl) butyric acid, an amino acid found in green tea (Camellia sinensis), is sold in the United States as a dietary supplement to reduce stress and improve cognition and mood. The observations that l-theanine has been shown to inhibit caffeine's stimulatory effects and that caffeine produces precipitated withdrawal signs in opioid-addicted monkeys and some opioid withdrawal signs in some normal monkeys, suggest that l-theanine may suppress opioid withdrawal signs. Additionally, l-theanine produces anxiolytic effects in humans indicating that it has anti-anxiety properties. Thus, in these studies we determined whether l-theanine attenuates opioid-withdrawal signs in morphine-dependent rhesus monkeys, a model for spontaneous opioid withdrawal in human opioid addicts. We also evaluated whether l-theanine decreases anxiety-like behavior in mice, using the elevated plus maze and marble burying assays. l-theanine significantly attenuated designated opioid withdrawal signs, including fighting, rigid abdominal muscles, vocalizing on palpation of abdomen, pacing, retching, wet-dog shakes, and masturbation. It had a relatively quick onset of action that persisted for at least 2.5h. l-theanine also produced anxiolytic-like effects in the elevated plus maze and the marble burying assay in naïve mice at doses that did not significantly affect motor behavior. The results of these studies suggest that l-theanine may be useful in the pharmacotherapy of treating opioid withdrawal as well as anxiety-associated behaviors.

Increased elevated plus maze open-arm time in mice during spontaneous morphine withdrawal

Rats undergoing both naloxone-precipitated and spontaneous opioid withdrawal exhibit anxiogenic behaviors in the elevated plus maze (EPM). Recently, we observed an unexpected result, namely mice exhibited increased EPM open-arm time during naloxone-precipitated morphine withdrawal. This was surprising since this behavioral outcome is usually associated with an anxiolytic profile. This study demonstrates that mice exhibit an increase in both EPM open-arm time and % open-arm entries also during spontaneous opioid withdrawal.

Experimentally‐Induced Spontaneous Opiate Withdrawal: Relationship to Cigarette Craving and Expired Air Carbon Monoxide

Smoking often increases after opioid use among those addicted to both opioids and nicotine, but the relationship between smoking and experimentally induced spontaneous opioid withdrawal (OW) has not been characterized. Six inpatient opioid-dependent smokers were stabilized on morphine 15 mg SC QID. Expired air carbon monoxide levels and smoking craving were measured for each participant on ten days when spontaneous OW was experimentally induced and on ten separate days in the absence of OW. Spontaneous OW was associated with significantly reduced carbon monoxide levels and smoking craving. Interestingly, craving was only reduced for items related to the positive reinforcing effects of smoking. These preliminary results suggest that OW may be a favorable context to initiate smoking cessation treatment interventions.

Modest opioid withdrawal suppression efficacy of oral tramadol in humans

Tramadol is in an unscheduled atypical analgesic with low rates of diversion and abuse and mixed pharmacologic actions, including modest opioid agonist activity. The purpose of the current study was to characterize the opioid withdrawal suppression efficacy of oral tramadol. Residential, opioid-dependent adults (n = 10) were maintained on morphine (15 mg subcutaneously, quad in diem) for approximately 6 weeks. Spontaneous opioid withdrawal was produced by substituting placebo for scheduled morphine doses 17.5 h before experimental sessions that occurred twice weekly. The acute effects of placebo, tramadol (50, 100, 200, and 400 mg orally), naloxone (0.1 and 0.2 mg intramuscularly [IM]), and morphine (15 and 30 mg IM) were tested under double-blind, double-dummy, randomized conditions. Outcomes included observer- and subject-rated measures, physiologic indices, and psychomotor/cognitive task performance. Naloxone and morphine produced prototypic opioid antagonist and agonist effects, respectively. Tramadol 50 and 100 mg produced effects most similar to placebo. Tramadol 200 and 400 mg initially produced significant dose-related increases in ratings of "bad effects" and "feel sick," followed by evidence of opioid withdrawal suppression. Tramadol did not produce significant increases on measures of positive drug effects nor any clinically significant physiologic changes. Tramadol 200 and 400 mg show evidence of opioid withdrawal suppression without significant observer- and subject-rated opioid agonist effects. The profile of action did not suggest a high risk for tramadol abuse in opioid dependent individuals. Tramadol may be a useful medication for treating opioid withdrawal.

Effects associated with double-blind omission of buprenorphine/naloxone over a 98-h period

Buprenorphine has a long duration of action that allows less than daily dosing for opioid dependence, but pharmacologic characterization of buprenorphine's duration of effects over multiple days is incomplete. This study assessed opioid blockade and spontaneous withdrawal effects of buprenorphine/naloxone (B/N) over a 98-h period. Residential opioid-dependent volunteers (n = 8) were maintained, in randomized sequence, on each of three different daily sublingual B/N doses (8/2, 16/4, 32/8 mg). After 2 weeks on each maintenance dose, participants underwent challenge sessions on each weekday for 1 week. Challenges consisted of within-session, ascending dose administration of IM hydromorphone (H: 0, 6, and 12 mg). During that week, active B/N dose was given only on Monday; double-blind placebo was administered on the remaining weekdays. Thus, these sessions assessed the extent of both opioid blockade and spontaneous withdrawal at 2, 26, 50, 74, and 98 h after the last active B/N dose. All three maintenance doses provided substantial but incomplete blockade against opioid agonist effects for 98 h. The extent of blockade diminished steadily but modestly over this time and did not differ as a function of B/N maintenance dose. In general, participants did not report marked spontaneous opioid withdrawal, although mild withdrawal effects were observed as time since the last active B/N dose increased. However, withdrawal did not differ as a function of B/N maintenance dose. These findings suggest that B/N doses greater than 8/2 mg provide minimal incremental value in terms of opioid blockade and withdrawal suppression.

Stimulation of mitogen-activated protein kinase kinases (MEK1/2) by μ-, δ- and κ-opioid receptor agonists in the rat brain: Regulation by chronic morphine and opioid withdrawal

Opioid addiction modulates the extracellular signal-regulated kinase (ERK) leading to synaptic plasticity in the brain. ERK1/2 are stimulated by mitogen-activated protein kinase kinases (MEK1/2), but little is known about the regulation of MEK activity by opioid drugs. This study was designed to assess the acute effects of selective μ-, δ-, and κ-opioid receptor agonists, as well as those induced by chronic morphine and opioid withdrawal, on the content of phosphorylated MEK1/2 in the rat brain. Sufentanil (1–30 μg/kg, 30–120 min) induced dose- and time-dependent increases in MEK1/2 phosphorylation in the cerebral cortex and corpus striatum (30–177%) through a naloxone-sensitive mechanism. Morphine (100 mg/kg, 2 h) also augmented MEK1/2 phosphorylation in the both brain regions (50–70%). Similarly, the selective δ-opioid receptor agonist SNC-80 (10 mg/kg, 30 min) increased MEK1/2 activity in the cortex (60%) that was antagonized by naltrindole. In contrast, the selective κ-opioid receptor agonist (−)-U50488H (10 mg/kg, 30–120 min) did not modify significantly MEK1/2 phosphorylation in the cortex. Chronic morphine (10–100 mg/kg, 5 days) was not associated with alterations in the content of phosphorylated MEK1/2 in the brain (induction of tachyphylaxis to the acute effects). In morphine-dependent rats, however, naloxone (2 mg/kg)-precipitated withdrawal (2–6 h) induced robust increases in MEK1/2 phosphorylation in cortex (27–49%) and striatum (83–123%). Spontaneous opioid withdrawal (24 h) in morphine-dependent rats did not alter MEK1/2 activity in the brain. The findings may be relevant in the context of the pivotal role played by the MEK/ERK pathway in various long-lasting forms of synaptic plasticity associated with opioid addiction.

Assessment of agonist and antagonist effects of tramadol in opioid-dependent humans.

The subjective, behavioral, and physiologic effects of racemic tramadol, an analgesic with low abuse liability and dual mu-opioid agonist and monoamine reuptake actions, were evaluated in 2 clinical pharmacology studies in dependent opioid abusers. In the withdrawal precipitation study, participants (N = 8) were maintained on methadone 60 mg/day orally and challenged with intramuscular tramadol, hydromorphone, naloxone, and placebo 20 hr after methadone administration. In the withdrawal suppression study, participants (N = 6) were maintained on hydromorphone given orally 10 mg 4 times daily, and spontaneous opioid withdrawal was produced by withholding doses for 23 hr. During the experimentally induced withdrawal, oral tramadol, hydromorphone, naltrexone, and placebo were given. In both studies a comprehensive panel of participant-rated, observer-rated, and physiologic measures were collected. In both studies, naloxone and naltrexone significantly increased measures of opioid withdrawal, whereas tramadol showed no discernible antagonist effects. In contrast, tramadol's pattern of effects was more similar to that of hydromorphone and suggestive of mild opioid-agonist effects (withdrawal suppression), though not to a statistically significant degree.

Effect of Remifentanil on Pain and Secondary Hyperalgesia Associated with the Heat–Capsaicin Sensitization Model in Healthy Volunteers

The heat--capsaicin sensitization model was developed as a noninvasive and noninjurious human experimental pain model. The sequential application of moderate intensity thermal and topical chemical stimuli produces stable and long-lasting areas of cutaneous secondary hyperalgesia. The aim of the present study was to validate the heat--capsaicin sensitization model as a tool for testing analgesic drug efficacy. Responsivity of model-associated measures was tested with remifentanil, a potent and ultrashort acting mu-opioid agonist. Sensitization was induced by heating forearm skin with a thermode at 45 degrees C for 5 min, immediately followed by application of 0.075% capsaicin cream for 30 min. Sensitization was rekindled four times at 40-min intervals with the thermode at 40 degrees C for 5 min. After each rekindling, areas of secondary hyperalgesia were measured, and the painfulness of thermal stimulation in normal skin with 45 degrees C for 1 min (long thermal stimulation [LTS]) was rated. Before and during the second rekindling, remifentanil 0.10 microg x kg(-1) x min(-1) or saline-placebo was infused for 35 min. Infusion of remifentanil reduced the areas of secondary hyperalgesia to 29--30% of baseline size compared with 75--83% during placebo. Similarly, remifentanil reduced the painfulness of LTS to 29% of baseline severity compared with 84% during placebo. Areas of secondary hyperalgesia and LTS painfulness returned to baseline levels by the time of the third rekindling, demonstrating rapid disappearance of remifentanil analgesia and possibly transient spontaneous opioid withdrawal hyperalgesia. Using the heat-capsaicin sensitization model, opioid analgesia and suppression of secondary hyperalgesia was reliably demonstrated without skin injury.

Cardiovascular changes during morphine administration and spontaneous withdrawal in the rat

Morphine maintenance doses of 10 mg kg −1 day −1, 20 mg kg −1 day −1 and 30 mg kg −1 day −1 were administered to three groups of rats via miniosmotic pumps for 7 days to induce physical dependence. They were then allowed to undergo spontaneous withdrawal. Radiotelemetric blood pressure measurements showed that morphine increased systolic and diastolic blood pressure on the first day of morphine treatment and produced a dose dependent decrease in heart rate, systolic and diastolic blood pressure thereafter. After the peak depressive effect, development of tolerance to morphine was observed in systolic and diastolic blood pressure, but not in the heart rate. During spontaneous withdrawal, both systolic and diastolic blood pressure increased beyond pre-morphine levels for all doses and there was a rebound increase in heart rate at the 30 mg kg −1 day −1 dose. These results suggest that the improved sensitivity of telemetric measures combined with the use of minipumps for morphine treatment provide an animal model of spontaneous opioid withdrawal.