Acute Opioid Withdrawal Research Articles

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Acute opioid withdrawal following administration of oral oxycodone–naloxone due to portosystemic shunts

AbstractBackgroundThe management of pain in patients with advanced liver disease is a clinical challenge. Initial pharmacokinetic safety data advised against the use of oxycodone–naloxone in this population, but in clinical practice it is commonly used. Our case aims to illustrate a potential mechanism by which administration of oxycodone–naloxone can cause systemic opioid antagonism and harm to patients.Clinical detailsA 45‐year‐old man received two separate doses of oxycodone–naloxone in the immediate postoperative setting, resulting in symptoms and signs consistent with acute opioid withdrawal. A review of his imaging revealed significant portosystemic shunts.OutcomesPortosystemic shunts in patients with advanced liver disease may lead to a decrease in the Phase II hepatic metabolism of naloxone and increased systemic levels. In the case of someone with pre‐existing opioid dependence, this may precipitate acute opioid withdrawal.ConclusionThe use of oxycodone–naloxone preparations should be avoided in patients with liver disease and portosystemic shunts.

Loperamide misuse to avoid opioid withdrawal and to achieve a euphoric effect: high doses and high risk

Introduction: Loperamide is a readily accessible nonprescription medication that is increasingly being used surreptitiously as an opioid substitute to alleviate the symptoms of acute opioid withdrawal. The objective of this study was to determine the clinical characteristics of patients with loperamide misuse and toxicity.Methods: The ToxIC registry, a nationwide, prospectively collected cohort of patients evaluated by medical toxicologists was searched from November 2011–December 2016 for patients with loperamide exposure. Each record was reviewed to determine the circumstances, dose, clinical presentations, treatment, and outcomes associated with loperamide use.Results: Twenty-six cases were identified, and both the absolute number and relative proportion of overall cases in the ToxIC registry increased annually. The median age was 27 and 54% were male. Of cases with known intent (n = 18), 12(67%) were misuse/abuse, 3(17%) were self-harm/suicide, and 3(17%) were pediatric exploratory ingestions. Circumstances for misuse included taking higher doses than labeled (n =7), avoiding withdrawal (n = 6), and gaining a pleasurable sensation (n =4). The dose was reported in nine cases and ranged from 4 mg to 400 mg. In patients seeking to avoid withdrawal doses were 160–400 mg/day; the most common reported dose was 200 mg. Reported ECG abnormalities included 10 cases of prolonged QTc (>500 ms), which consisted of misuse/abuse (n =6) and self-harm (n =1) exposures; six prolonged QRS (>120 ms); two first degree AV block; seven ventricular dysrhythmias, five of which were single-agent exposures. All but one ECG demonstrated prolonged QTc with a range of 566–749 ms. All patients with dysrhythmias in which dose were reported ingested ≥200 mg.Conclusions: The majority of patients had loperamide toxicity due to misuse/abuse, in-line with national trends. In patients avoiding withdrawal, doses >100 mg were observed. When taken in large doses (>200 mg), loperamide may cause significant cardiovascular effects, including QTc-prolongation and ventricular dysrhythmias.

The LASSO Program in Oslo: Harm Reduction Using Buprenorphine-Naloxone (Suboxone®) in a Low Threshold Setting

Background: This is a 6-year retrospective quality control study of the LASSO Program (Low Threshold Substitution Treatment in Oslo), using exclusively Suboxone® (buprenorphine-naloxone [BPNX]) in out-patient settings. Adequate abstinence prior to induction is necessary to avoid acute onset opioid withdrawal symptoms; thus, its use in low threshold settings is far less common than methadone. Objectives: The aim of this study was to determine if BPNX is a safe and feasible medication to use in a low threshold setting. Methods: The analysis is based on daily supervised BPNX medication. The standardized induction regime started with 4-mg BPNX increasing by 4 mg daily until 16 mg, with individual adjustments based on clinical status. Treatment effect was evaluated by the number of medication induction attempts, treatment length and lag time between initial contact and medication start. Statistical computations were performed with SPSS®. Results: There were 331 out of 394 registered patient inquires that started on BPNX. Two hundred fifty-three patients (76.4%) completed induction on first attempt with 95% Wilson score CIs of (0.716–0.807). The accumulated percentage increased to 85.2% during successive inductions. No significant association was found between lag time and (i) the number of days on medication during the first induction; or (ii) total treatment length. Patients had a median lag time of 5 days, remained in treatment a median of 52.0 days with an average of 3.9 inductions. There were no cases of severe precipitated withdrawal and only 2 cases of adverse reactions among the 1,293 inductions and 25,544 administered dosages. Conclusion: This study shows that BPNX is highly effective in treating marginalized heroin addicts in low threshold settings. Even during their first attempt, 76.4% completed induction. There were no cases of severe precipitated withdrawal. Prolonged lag time affected neither the length of first treatment nor the total treatment length. Individualized induction readiness approach and motivation were central to the above results.

Biosynthetically Inspired Transformation of Iboga to Monomeric Post-iboga Alkaloids

Summary Organisms have evolved to produce various natural products from a common precursor as a means of maximizing the number of secondary metabolites, thus acquiring selectional advantages. By adopting nature's divergent biosynthetic strategy, we transformed (+)-catharanthine to various iboga and post-iboga alkaloids, including (−)-conodusine A, (+)-conodusines B and C, (−)-voatinggine, (−)-tabertinggine, and (+)-dippinine B. Well-orchestrated oxidations and reorganizations of catharanthine derivatives enabled chemical access to these natural products.

Decrease of inhibitory synaptic currents of locus coeruleus neurons via orexin type 1 receptors in the context of naloxone-induced morphine withdrawal.

Acute opioid withdrawal syndrome is a series of neurological symptoms caused by the abrupt cessation of the chronic administration of opioids such as morphine. The locus coeruleus (LC) in the brain stem receives a dense projection of orexinergic fibers from the hypothalamus and is a candidate site for the expression of the somatic aspects of morphine withdrawal. Previous studies have shown that orexin-A contributes to the behavioral symptoms of naloxone-induced morphine withdrawal, partly by reducing the activity of GABAergic neurons, suggesting that orexin-A may negatively modulate fast GABAergic neurotransmission during morphine withdrawal. We used whole-cell patch-clamp recordings of LC neurons in brainstem slices to investigate the effect of orexin-A on bicuculline-sensitive GABAergic inhibitory postsynaptic currents (IPSCs) during naloxone-induced morphine withdrawal. Male Wistar rats (P14-P21) were given morphine (20mg/kg, i.p.) daily for seven consecutive days to create dependency on the drug. The application of naloxone (1µM) to brain slices of morphine-treated rats reduced the amplitude of evoked IPSCs (eIPSCs) as well as spontaneous IPSCs (sIPSCs) frequency but did not change sIPSCs amplitude. Orexin-A (100nM) significantly enhanced the suppressive effect of naloxone on eIPSCs amplitude and sIPSCs frequency but had no effect on the presence of the orexin type 1 receptor (OX1R) antagonist, SB-334867. Orexin-A alone had no significant effect on eIPSCs and sIPSCs in the absence of naloxone. In summary, our results show that orexin-A, via OX1R, potentiates the suppressive effect of naloxone on GABAergic IPSCs of LC neurons in morphine-treated rats. We conclude that orexins may have a critical role in regulating GABAergic neurotransmission to LC neurons during naloxone-induced morphine withdrawal.

A retrospective chart review of outcomes resulting from a three-day tramadol taper for acute opioid withdrawal

The purpose of the study was to describe patient outcomes with a 3-day tramadol taper for acute opioid withdrawal on the detoxification unit at Summa Health System. The primary endpoint was the change in Clinical Institute Narcotic Assessment (CINA) score from the start of the taper until completion or discharge. Secondary endpoints were length of stay, use of adjuvant medications, taper completion rates, highest CINA score, adverse events, and 30-day readmission rates. A retrospective, quality improvement, cohort study was performed describing outcomes of opioid dependent patients in acute withdrawal admitted on the detoxification unit between September 2014 and September 2016 receiving the 3-day tramadol taper. All patients ≥18 years of age admitted for opioid dependence were included. Pregnant patients were excluded. Forty-five patients were included in the analysis. Patient ages ranged from 18-67 and 25 (55.6%) were male. The full taper was completed in 67.7% of admissions and 75.8% of patients were discharged by the physician. There was a statistically significant change of the pre-taper score compared to the score at completion or discharge in the per protocol group (-1.58, p = 0.010). There were no reported seizures or falls. The 3-day tramadol taper proved to be safe and effective therapy for treating acute opioid withdrawal. In the Summa Health System detoxification unit, patients treated with a 3-day tramadol taper for acute opioid withdrawal had their pre-taper CINA scores reduced by over 25% at the completion of the taper or discharge.

LO27: Improving emergency department management of acute opioid withdrawal

Introduction: With the current opioid crisis in Canada, presentations of acute opioid withdrawal (AOW) to emergency departments (ED) are increasing. Undertreated symptoms may result in relapse, overdose and death. Buprenorphine/naloxone (bup/nal) is a partial opioid agonist/antagonist used to mitigate symptoms of AOW, approved by Health Canad in 2007 for opioid use disorder. It is superior to clonidine, and increases follow up with addiction treatment programs when initiated in the ED. Nevertheless, in our inner-city ED in 2014, bup/nal was rarely prescribed. We aimed to increase ED physician prescribing of bup/nal for AOW by 50% over a 26-month period. Methods: Commencing in 2014, an interprofessional team of ED physicians, nurses (RN), pharmacists and QI specialists collaborated to improve the care of patients with AOW. PDSA cycles included: (1) needs assessment of emergency physicians knowledge and practices in 2014; (2) Grand Rounds and a web based information sheet in 2015; (3) ED stocking of bup/nal; (4) convenience order set to standardize AOW management; (5) Grand Rounds in 2016 and (6) peer-coaching for RNs, including case-based discussions and pocket card cognitive aids. The outcome was the number of times bup/nal was prescribed per month by ED physicians between Sept, 2015 and Oct, 2017. Data included the prescriber and use of order set as the process measure. The balancing measure was the number of patients referred to the Addiction Medicine Team who subsequently received bup/nal. Results: Bup/nal was prescribed by ED physicians 70 times, and 14 times by the Addiction Medicine Team. With each PDSA cycle, there was an increase in prescribing, with no significant shifts or trends. By all physicians, the median number of prescriptions per month was 3, and increased from 2 to 4 prescriptions/month after nursing education. There was a smaller increase in the median from 2 to 3 prescriptions/month by ED physicians alone. The order set was used 97% of the time. Conclusion: Bup/nal is safe, effective, and increases follow up with addiction programs for comprehensive assessment and treatment planning. We met our goal of increasing bup/nal prescribing in the ED for AOW by 50%. Moreover, prescribing increased by 100% with the addition of patients who received bup/nal after a referral to the Addiction Medicine Team. The intervention with the greatest impact was RN education, demonstrating that peer-coaching and teaching by an interprofessional team is key to changing practice. Unfortunately, overall prescribing remains low, and ED physicians may still be hesitant to prescribe bup/nal and defer to the specialists. It is unclear if this is due to a low number of patients presenting with AOW, patients with contraindications to bup/nal, or ED physician factors. The next step is an audit of all patients with AOW to see what percentage of those eligible are treated with bup/nal. A follow up survey to determine ongoing barriers will inform further PDSA cycles.

Postanaesthetic shivering – from pathophysiology to prevention

Postoperative shivering is a common complication of anaesthesia. Shivering is believed to increase oxygen consumption, increase the risk of hypoxemia, induce lactic acidosis, and catecholamine release. Therefore, it might increase the postoperative complications especially in high-risk patients. Moreover, shivering is one of the leading causes of discomfort for postsurgical patients. Shivering is usually triggered by hypothermia. However, it occurs even in normothermic patients during the perioperative period. The aetiology of shivering has been understood insufficiently. Another potential mechanism is pain and acute opioid withdrawal (especially with the use of short-acting narcotics). Besides that shivering is poorly understood, the gold standard for the treatment and prevention has not been defined yet. Perioperative hypothermia prevention is the first method to avoid shivering. Many therapeutic strategies for treating shivering exist and most are empiric. Unfortunately, the overall quality of the antishivering guidelines is low. Two main strategies are available: pharmacological and non-pharmacological antishivering methods. The combination of forced-air warming devices and intravenous meperidine is the most validated method. We also analysed different medications but final conclusion about the optimal antishivering medication is difficult to be drawn due to the lack of high-quality evidence. Nevertheless, control of PS is possible and clinically effective with simple pharmacological interventions combined with non pharmacological methods. However, to be consistent with the most up-to-date, evidence-based practice, future antishivering treatment protocols should optimize methodological rigor and transparency.

Altered Signaling in the Descending Pain-modulatory System after Short-Term Infusion of the μ-Opioid Agonist Remifentanil.

μ-Opioid receptor agonists are widely used within the contemporary treatment of pain, but abrupt opioid suspension, even after short-term infusion, can paradoxically increase the sensitivity to noxious stimuli, a phenomenon that has been, for example, reported after application of the fast-acting μ-opioid receptor agonist remifentanil. To investigate the mechanisms underlying the effects of discontinuation of remifentanil application on pain processing in the human CNS, we analyzed neuronal responses to thermal stimuli before and after a short-term infusion of remifentanil (30 min 0.1 μg/kg body weight/min) compared with control in the brain, brainstem, and spinal cord in drug-naive male volunteers using fMRI. Subsequent to remifentanil suspension, we observed reduced heat pain thresholds and increased neuronal responses in pain-encoding as well as in key regions of the descending pain-modulatory system, such as the periaqueductal gray matter, the nucleus cuneiformis, and the rostral ventromedial medulla. Moreover, the spinal pain-related multivoxel activity pattern showed an opioid-specific change after drug suspension. Importantly, remifentanil suspension increased the functional coupling between the nucleus cuneiformis and the rostral anterior cingulate cortex, and the coupling strength between the rostral anterior cingulate cortex and the nucleus cuneiformis correlated negatively with the individual pain threshold after opioid suspension. These findings demonstrate that, already subsequent to a short-term infusion of the μ-opioid receptor agonist remifentanil, signaling in the descending pain-modulatory system is fundamentally altered and that these changes are directly related to the behavioral sensitivity to pain.SIGNIFICANCE STATEMENT Opioids are widely used in modern medicine, but, in addition to their known side effects, it is increasingly recognized that opioids can also increase sensitivity to pain subsequent to their use. Using the fast-acting μ-opioid receptor agonist remifentanil and fMRI in healthy male volunteers, this study demonstrates how signaling changes occur along the entire descending pain-modulatory pathway after opioid discontinuation and how these alterations are closely linked to increased behavioral pain sensitivity. Particularly by revealing modified responses in pain-modulatory brainstem regions that have been previously demonstrated to be causally involved in acute opioid withdrawal effects in rodents, the data provide a plausible neuronal mechanism by which the increased sensitivity to pain after opioid suspension is mediated in humans.

Opioid-induced hyperalgesia in clinical anesthesia practice: what has remained from theoretical concepts and experimental studies?

This article reviews the phenomenon of opioid-induced hyperalgesia (OIH) and its implications for clinical anesthesia. The goal of this review is to give an update on perioperative prevention and treatment strategies, based on findings in preclinical and clinical research. Several systems have been suggested to be involved in the pathophysiology of OIH with a focus on the glutaminergic system. Very recently preclinical data revealed that peripheral μ-opioid receptors (MORs) are key players in the development of OIH and acute opioid tolerance (AOT). Peripheral MOR antagonists could, thus, become a new prevention/treatment option of OIH in the perioperative setting. Although the impact of OIH on postoperative pain seems to be moderate, recent evidence suggests that increased hyperalgesia following opioid treatment correlates with the risk of developing persistent pain after surgery. In clinical practice, distinction among OIH, AOT and acute opioid withdrawal remains difficult, especially because a specific quantitative sensory test to diagnose OIH has not been validated yet. Since the immediate postoperative period is not ideal to initiate long-term treatment for OIH, the best strategy is to prevent its occurrence. A multimodal approach, including choice of opioid, dose limitations and addition of nonopioid analgesics, is recommended.

Imaging Sex Differences in Regional Brain Metabolism during Acute Opioid Withdrawal.

The rate of opioid overdose continues to rise, necessitating improved treatment options. Current therapeutic approaches rely on administration of either a blocking agent, such as naloxone, or chronic treatment with replacement drugs, including methadone and/or buprenorphine. Recent findings suggest that males and females respond to these treatments uniquely. In an effort to better understand this sex-specific variation in treatment efficacy, we investigated the effects of acute opioid withdrawal in male and female rats using 18FDG and microPET. These data demonstrate that acute opioid withdrawal produces metabolic alterations in brain regions associated with reward and drug dependence, namely corpus striatum, thalamic nuclei, septum, and frontal cortex. Furthermore, certain changes are unique to males. Specifically, males demonstrated increased metabolism in the anterior cingulate cortex and the ventral hippocampus (CA3) following acute opioid withdrawal. If males and females exhibit sex-specific changes in regional brain metabolism following acute opioid withdrawal, then perhaps it is not surprising that they respond to treatment differently.

Clinical, Ethical, and Legal Considerations in Pregnant Women With Opioid Abuse

(Obstet Gynecol. 2015;126:474–478) Opioid-dependent pregnant women who undergo acute opioid withdrawal during pregnancy are at increased risk for miscarriage, placental abruption, preterm labor, and stillbirth. Physicians should thus have basic familiarity with the medical, ethical, and legal issues surrounding opioid maintenance therapy, which mitigates the risks of frequent withdrawal during gestation and reduces the risk of relapse after delivery. Longer-lasting therapies like methadone and buprenorphine can increase accessibility to care for this population all while preserving confidentiality, decreasing social stigma, and reducing lengthy resource-intensive hospitalizations. Other benefits include lowered risk of bloodborne infection transmission and improved maternal and neonatal health outcomes.

Palonosetron and hydroxyzine pre-treatment reduces the objective signs of experimentally-induced acute opioid withdrawal in humans: a double-blinded, randomized, placebo-controlled crossover study

ABSTRACTBackground: Treatments for reducing opioid withdrawal are limited and prone to problematic side effects. Laboratory studies, clinical observations, and limited human trial data suggest 5-HT3-receptor antagonists and antihistamines may be effective. Objectives: This double-blind, crossover, placebo-controlled study employing an acute physical dependence model evaluated whether (i) treatment with a 5-HT3-receptor antagonist (palonosetron) would reduce opioid withdrawal symptoms, and (ii) co-administration of an antihistamine (hydroxyzine) would enhance any treatment effect. Methods: At timepoint T = 0, healthy (non-opioid dependent, non-substance abuser) male volunteers (N = 10) were pre-treated with either a) placebo, b) palonosetron IV (0.75 mg), or c) palonosetron IV (0.75 mg) and hydroxyzine PO (100 mg) in a crossover study design. This was followed at T = 30 by intravenous morphine (10 mg/70kg). At T = 165, 10 mg/70kg naloxone IV was given to precipitate opioid withdrawal. The objective opioid withdrawal score (OOWS) and subjective opioid withdrawal score (SOWS) were determined 5 and 15 minutes after naloxone administration (T = 170, 180, respectively). Baseline measurements were recorded at T = −30 and T = −15. Results: Comparison of average baseline OOWS scores with OOWS scores obtained 15 minutes after naloxone was significant (p = 0.0001). Scores from 15 minutes post-naloxone infusion showed significant differences in OOWS scores between treatment groups: placebo, 3.7 ± 2.4; palonosetron, 1.5 ± 0.97; and palonosetron with hydroxyzine, 0.2 ± 0.1333. Conclusions: Pretreatment with palonosetron significantly reduced many signs of experimentally-induced opioid withdrawal. Co-administration with hydroxyzine further reduced opioid withdrawal severity. These results suggest that 5-HT3 receptor antagonists, alone or in combination with an antihistamine, may be useful in the treatment of opioid withdrawal.

Psychometric evaluation of the 10-item Short Opiate Withdrawal Scale-Gossop (SOWS-Gossop) in patients undergoing opioid detoxification

IntroductionThe Short Opiate Withdrawal Scale (SOWS)-Gossop is a 10-item questionnaire developed to evaluate opioid withdrawal symptom severity. The scale was derived from the original 32-item Opiate Withdrawal Scale in order to reduce redundancy while providing an equally sensitive measure of opioid withdrawal symptom severity appropriate for research and clinical practice. The objective of this study was to examine the psychometric properties and provide score interpretation guidelines for the SOWS-Gossop 10-item version. MethodsBlinded, pooled data from two trials assessing the efficacy of lofexidine hydrochloride in reducing withdrawal symptoms in patients undergoing opioid detoxification were used to evaluate the quantitative psychometric properties and score interpretation of the SOWS-Gossop. ResultsFive hundred fifty-five (N=555) observations were available at baseline with numbers decreasing to n=213 at day 7. Mean (standard deviation) SOWS-Gossop scores were 10.4 (6.86) at baseline, 8.7 (6.49) on day 1, 10.5 (7.21) on day 2, and 3.1 (3.95) on day 7. Confirmatory factor analysis indicated that the SOWS-Gossop items loaded on a single factor consistent with a single total score. Intra-class correlations (95% confidence interval) were 0.78 (0.70–0.85) between baseline and day 1, 0.84 (0.79–0.89) between days 4 and 5, and 0.88 (0.83–0.91) between days 6 and 7, demonstrating good test-retest reliability. Mean SOWS-Gossop scores varied significantly (p<0.0001) by Modified Clinical Global Impression severity groups supporting known-groups validity. Most correlations with conceptually similar instruments were over 0.4, providing evidence of construct validity. Results suggest that a change score of approximately 2–4 points is likely a small but meaningful improvement on the SOWS-Gossop Total Score. ConclusionsThe findings of this study indicate that the SOWS-Gossop includes concepts that are relevant to patients' experiences with opioid withdrawal and has excellent psychometric properties. The SOWS-Gossop is an appropriate, precise, and sensitive measure to evaluate the symptoms of acute opioid withdrawal in research or clinical settings.

Assessment of the appropriateness of naloxone administration to patients receiving long-term opioid therapy

ABSTRACTBackground: The most dangerous adverse effect of opioids is respiratory depression. Naloxone is used to reverse this, although in patients receiving long-term opioid therapy it can cause acute opioid withdrawal and opioid-refractory pain.Objective: To determine if naloxone is appropriately administered to patients receiving long-term opioid therapy.Methods: This retrospective case series based on chart reviews systematically identified patients over one year in a district general hospital. All patients aged 18 years or older receiving long-term opioid therapy admitted to medicine, surgery or the high dependency unit who were administered naloxone during their admission were included.Results: A total of 1206 patient drug administration records were reviewed. Sixteen patients receiving long-term opioid therapy were administered naloxone. Twelve of these did not have opioid-induced respiratory depression and four did not have respiratory rate and oxygen saturations documented in the medical notes. All naloxone doses administered were higher than those recommended by national guidelines for this patient group.Conclusions: No patient receiving long-term opioid therapy who was administered naloxone had evidence of respiratory depression. More thorough assessment and documentation are needed. Verbal and physical stimulation as well as oxygenation should be considered prior to naloxone administration; this should be followed by close observation, hydration, renal function tests and opioid dose review.

Reversal of Opioid-Induced Ventilatory Depression Using Low-Dose Naloxone (0.04mg): a Case Series.

Naloxone is commonly administered in emergency department (ED) to reverse opioid intoxication. Several naloxone dose recommendations exist for acute management of opioid intoxication based on limited published clinical data. A case series of ED patients with opioid-induced ventilatory depression that was reversed using a low-dose naloxone (0.04mg with titration) is presented. ED patients with opioid-induced ventilatory depression requiring naloxone administration were identified through medical toxicology consultation. Retrospective review of medical records was performed. Collected data included history, and pre- and post-naloxone data, including respiratory rate (RR), pulse oximetry (pulse ox), end-tidal CO2 level (ET-CO2), and Richmond Agitation Sedation Scale (RASS). Fifteen ED patients with moderate to severe opioid-induced ventilatory depression (median RR, 6breaths/min) who were managed using low-dose naloxone strategy were identified. Twelve of 15 patients reported ingestion of methadone (range, 30 to 180mg). The median naloxone dose of 0.08mg (range, 0.04 to 0.12mg) reversed opioid-induced ventilatory and CNS depression. Two patients experienced acute opioid withdrawal after receiving 0.08mg. ED patients with moderate to severe opioid-induced ventilatory depression can be reversed using 0.04mg IV naloxone with appropriate dose titration.

Oxycodone/naloxone preparation can cause acute withdrawal symptoms when misused parenterally or taken orally

Context. Oral oxycodone/naloxone preparations are designed to reduce the incidence of constipation associated with oxycodone use. The low oral bioavailability (< 2%) of naloxone makes the precipitation of the acute opioid withdrawal symptoms unlikely following oral oxycodone/naloxone exposure. The incidence of acute opioid withdrawal symptoms following both oral and intravenous administration of oxycodone/naloxone preparations has not been described. Objective. The aim of the study was to investigate the incidence and circumstances associated with oxycodone/naloxone-induced acute opioid withdrawal. Methods. An observational case series of acute opioid withdrawal following oxycodone/naloxone administration were selected from all calls received by the Victoria Poisons Information Centre from January 2012 to December 2014. Data collected included patient demographics, reported symptoms, type of caller, intentional or accidental exposure and advice given. Results. There were 107 reported exposures to oxycodone/naloxone preparations. Route of exposure was oral in 92 (86%) and intravenous injection of crushed tablets in 14 (14%) of cases, respectively. Nine callers had a history of long-standing opioid treatment and developed withdrawal symptoms with oral oxycodone/naloxone. Temporal relationship between first dose, increased dose and chewing tablets was described. There were 14 exposures to crushed oxycodone/naloxone tablets injected intravenously; all precipitated an acute withdrawal state. Discussion. The development of opioid withdrawal symptoms with intravenous injection of oxycodone/naloxone is likely a result of bypassing first-pass metabolism. Withdrawal symptoms after ingesting increased dose, first dose or chewing oxycodone/naloxone suggests that there is a systemic absorption of naloxone in opioid-dependent callers. Conclusion. Oxycodone with naloxone tablets can lead to acute opioid withdrawal symptoms if crushed and injected parentally. First dose, increased dose and chewing of these opioid–naloxone combination tablets in opioid-dependent people can also result in acute opioid withdrawal symptoms or diminished pain relief.

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.

Acute opioid withdrawal is associated with increased neural activity in reward-processing centers in healthy men: A functional magnetic resonance imaging study

BackgroundOpioid analgesics are frequently prescribed for chronic pain. One expected consequence of long-term opioid use is the development of physical dependence. Although previous resting state functional magnetic resonance imaging (fMRI) studies have demonstrated signal changes in reward-associated areas following morphine administration, the effects of acute withdrawal on the human brain have been less well-investigated. In an earlier study by our laboratory, ondansetron was shown to be effective in preventing symptoms associated with opioid withdrawal. The purpose of this current study was to characterize neural activity associated with acute opioid withdrawal and examine whether these changes are modified by ondansetron. MethodsTen participants were enrolled in this placebo-controlled, randomized, double-blind, crossover study and attended three acute opioid withdrawal sessions. Participants received either placebo or ondansetron (8mg IV) before morphine administration (10mg/70kg IV). Participants then underwent acute naloxone-precipitated withdrawal during a resting state fMRI scan. Objective and subjective opioid withdrawal symptoms were assessed. ResultsImaging results showed that naloxone-precipitated opioid withdrawal was associated with increased neural activity in several reward processing regions, including the right pregenual cingulate, putamen, and bilateral caudate, and decreased neural activity in networks involved in sensorimotor integration. Ondansetron pretreatment did not have a significant effect on the imaging correlates of opioid withdrawal. ConclusionsThis study presents a preliminary investigation of the regional changes in neural activity during acute opioid withdrawal. The fMRI acute opioid withdrawal model may serve as a tool for studying opioid dependence and withdrawal in human participants.