Low-dose Methadone Research Articles

Low-dose methadone added to another opioid for cancer pain: a multicentre prospective study

ContextThe use of methadone for cancer pain management is gaining wider acceptance. However, switching to methadone treatment can still pose challenges. Consequently, there is ongoing development of its use in low doses in combination with other opioids, despite a lack of clinical evidence regarding its efficacy and safety.ObjectivesThis study aimed to evaluate the efficacy and tolerability of low-dose methadone in combination with another opioid in patients with moderate-to-severe cancer-related pain in a clinical setting.Patients and methodsThis was a prospective, open-label study conducted in 19 pain and/or palliative care centres treating patients with cancer-related pain. Pain intensity, patients' global impression of change, and adverse effects were assessed on day 7 and day 14. The main outcome measure was the proportion of responders.ResultsThe study included 92 patients. The daily dose of methadone was 3 [3–6] mg at baseline, 9 [4–10] mg on day 7 and 10 [6–15] mg on day 14. The NRS pain ratings significantly decreased from 7 [6–8] at baseline to 5 [3–6] on visit 2 (p < .0001) and 4 [3–6] on visit 3 (p < .0001). Similarly, the VRS pain ratings decreased from 3 [3–3] at baseline to 2 [2–3] on visit 2 (p = 0.026) and 2 [1–3] (p < 0.001) on visit 3. At Visits 1 and 2, half of the patients were considered Responders. Of those responders, 73.5% were High-Responders at Visit 1 and 58.7% were High-Responders at Visit 2. No adverse events related to the risk of QT prolongation, overdose, or drug interactions were reported.ConclusionFor patients experiencing moderate to severe cancer-related pain despite initial opioid treatment, our study found that low-dose methadone, when used in combination with another opioid, was both safe and effective. This supports the use of methadone as an adjunct to opioid-based treatment for cancer pain.

Impact of chronic opioid on cognitive function and spermatogenesis in rat: An experimental study.

Opioid analgesics like morphine and methadone are widely used for managing severe pain; however, concerns over their potential misuse and adverse effects on the brain and reproductive system are significant. We aimed to investigate their impacts on spermatogenesis and cognitive function in male Norway rats. In this experimental study, 36 male Norway rats (250-300 gr, 6 months old) were divided into 6 groups: low-dose morphine, high-dose morphine, low-dose methadone, high-dose methadone, positive control (received normal saline at 5 mg/kg), and negative control (received no treatment). Morphine and methadone were administered intraperitoneally over 30 days at doses of 3 mg/kg and 7 mg/kg, respectively. Behavioral assessments evaluated anxiety, stress, and short- and long-term memory. Sperm parameters (viability, motility, morphology), hormonal analysis (testosterone, luteinizing hormone, follicle-stimulating hormone, estradiol), and gene expressions (Tp53, CatSper1) were assessed. A significant reduction in rat weight was observed in the high-dose morphine group (p = 0.0045), while testicular weights remained unchanged. Sperm abnormalities were observed with high doses of methadone and morphine. High-dose methadone significantly reduced offspring count (p = 0.0004). Levels of follicle-stimulating hormone, luteinizing hormone, testosterone, and estradiol varied significantly across treatment groups. Gene expression was altered in response to treatments (p 0.05). Prolonged exposure to methadone and morphine resulted in memory dysfunction, chronic stress, hormonal disturbances, altered gene expression, and fertility complications. These effects were more pronounced at higher doses, highlighting the importance of careful dosage management in opioid therapy.

A preliminary investigation of the acute effects of delta-9-tetrahydrocannabinol on pain and opioid attentional bias among persons with opioid use disorder

IntroductionAttentional bias (AB) is believed to be an important factor in the development and maintenance of both opioid use disorder (OUD) and chronic pain. Cannabis and its main psychoactive constituent, delta-9-tetrahydrocannabinol (THC), produce analgesic effects via processes that are potentially relevant to AB and is commonly used by persons with OUD. This exploratory study investigated if THC influences AB towards pain and opioid cues individuals with OUD. MethodsUsing a within-subject, crossover design, 27 adults receiving methadone were randomly assigned to receive single doses of oral THC (10 mg, 20 mg administered as dronabinol) or placebo across three, 5-h sessions. During each session, a visual probe task was used to measure AB to pain and opioid cues at baseline and 120 min post-THC administration. ResultsMixed-effects models examined main effects of THC dose, time, and their interaction across all participants; findings were then stratified by methadone dose (low dose <90 mg/day and high dose ≥90 mg/day). Among individuals receiving high doses of methadone, a significant interaction was observed such that AB towards opioids increased following 10 mg THC administration and decreased following 20 mg THC administration. Additionally, participants receiving low doses of methadone showed significant increases in the variability of opioid-related AB post THC administration. ConclusionWe provide preliminary evidence showing that THC may cause dose-dependent effects on selective attention for opioid cues among methadone patients. These results underscore the need for further clinical investigation into the effects of cannabinoids and other substances with potential analgesic and addictive properties among persons with OUD.

Utility of Low-Dose Methadone for Chronic Dyspnea: A Case Series

Utility of Low-Dose Methadone for Chronic Dyspnea: A Case Series

A case with a trend of QT interval prolongation due to the introduction of methadone to a pancreatic cancer patient on levofloxacin

BackgroundAs methadone can prevent the development of opioid resistance, it has application in alleviating cancer-related pain that proves challenging to manage with other opioids. QT interval prolongation is a serious side effect of methadone treatment, with some reported deaths. In particular, owing to the increased risk of QT interval prolongation, caution should be exercised when using it in combination with drugs that also prolong the QT interval.Case presentationThis study presents a case in which methadone was introduced to a patient (a man in his 60s) already using levofloxacin, which could prolong the QT interval—a serious side effect of methadone treatment—and whose QTc value tended to increase. Given that levofloxacin can increase the risk of QT interval prolongation, we considered switching to other antibacterial agents before introducing methadone. However, because the neurosurgeon judged that controlling a brain abscess was a priority, low-dose methadone was introduced with continuing levofloxacin. Owing to the risks, we performed frequent electrocardiograms. Consequently, we responded before the QTc increased enough to meet the diagnostic criteria for QT interval prolongation. Consequently, we prevented the occurrence of drug-induced long QT syndrome.ConclusionsWhen considering the use of methadone for intractable cancer pain, it is important to eliminate possible risk factors for QT interval prolongation. However, as it may be difficult to discontinue concomitant drugs owing to comorbidities, there could be cases in which the risk of QT interval prolongation could increase, even with the introduction of low-dose methadone. In such cases, frequent monitoring, even with simple measurements such as those used in this case, is likely to prevent progression to more serious conditions.

Biochemical differences between high and low dose methadone clients on stable maintenance therapy

The methadone dose required to prevent withdrawal symptoms in chronic methadone users varies dramatically from 5 to 300 mg/day, which could be attributed to a number of biochemical factors, including human µ-opioid receptor (hMOR) density, down-stream desensitization, concurrent drug use or P-glycoprotein (P-gp) expression, or other, possibly genetic factors. Here we describe some biochemical changes of patients taking higher versus lower doses in chronic methadone maintenance therapy (MMT). hMOR density was measured in leukocytes from methadone-maintained patients receiving lower dose (&lt;100 mg/day) or higher dose (≥100 mg/day) and naive subjects by flow cytometry. Desensitization of receptor signaling was examined by measuring in vivo and attenuated cyclic AMP (cAMP) levels in response to increasing methadone concentrations. P-gp expression and the presence of other drugs were measured using validated methods.

Neonatal opioid toxicity: opioid withdrawal (abstinence) syndrome with emphasis on pharmacogenomics and respiratory depression.

The increasing use of opioids in pregnant women has led to an alarming rise in the number of cases of neonates with drug-induced withdrawal symptoms known as neonatal opioid withdrawal syndrome (NOWS). NOWS is a toxic heterogeneous condition with many neurologic, autonomic, and gastrointestinal symptoms including poor feeding, irritability, tachycardia, hypertension, respiratory defects, tremors, hyperthermia, and weight loss. Paradoxically, for the management of NOWS, low doses of morphine, methadone, or buprenorphine are administered. NOWS is a polygenic disorder supported by studies of genomic variation in opioid-related genes. Single-nucleotide polymorphisms (SNPs) in CYP2B6 are associated with variations in NOWS infant responses to methadone and SNPs in the OPRM1, ABCB1, and COMT genes are associated with need for treatment and length of hospital stay. Epigenetic gene changes showing higher methylation levels in infants and mothers have been associated with more pharmacologic treatment in the case of newborns, and for mothers, longer infant hospital stays. Respiratory disturbances associated with NOWS are not well characterized. Little is known about the effects of opioids on developing neonatal respiratory control and respiratory distress (RD), a potential problem for survival of the neonate. In a rat model to test the effect of maternal opioids on the developing respiratory network and neonatal breathing, maternal-derived methadone increased apneas and lessened RD in neonates at postnatal (P) days P0 and P1. From P3, breathing normalized with age suggesting reorganization of respiratory rhythm-generating circuits at a time when the preBötC becomes the dominant inspiratoryrhythm generator. In medullary slices containing the preBötC, maternal opioid treatment plus exposure to exogenous opioids showed respiratory activity was maintained in younger but not older neonates. Thus, maternal opioids blunt centrally controlled respiratory frequency responses to exogenous opioids in an age-dependent manner. In the absence of maternal opioid treatment, exogenous opioids abolished burst frequencies at all ages. Prenatal opioid exposure in children stunts growth rate and development while studies of behavior and cognitive ability reveal poor performances. In adults, high rates of attention deficit disorder, hyperactivity, substance abuse, and poor performances in intelligence and memory tests have been reported.

Severe Myoclonus and Altered Mental Status Secondary to Low-Dose Methadone (CS351)

Severe Myoclonus and Altered Mental Status Secondary to Low-Dose Methadone (CS351)

Regular, low-dose methadone for reducing breathlessness in people experiencing or at risk of neurotoxic effects from morphine: A single-center case series.

Breathlessness is a common symptom suffered by people living with advanced malignant and non-malignant diseases, one which significantly limits their quality of life. If it emerges at minimal exertion, despite the maximal, guidelines-directed, disease-specific therapies, it should be considered persistent and obliges clinicians to prescribe symptomatic, non-pharmacological, and pharmacological treatment to alleviate it. Opioids are recommended for the symptomatic treatment of persistent breathlessness, with morphine most extensively studied for this indication. It is extensively metabolized in the liver into water-soluble 3- and 6-glucuronides, excreted by the kidneys. In the case of advanced renal failure, the glucuronides accumulate, mainly responsible for toxicity 3-glucuronides. Some people, predominantly those with advanced renal failure, develop neurotoxic effects after chronic morphine, even when prescribed at a very low dose. A single-center case series of consecutive patients experiencing neurotoxic effects after long-term, low-dose morphine or at risk of such effects were transferred to methadone to avoid the accumulation of neurotoxic metabolites. Over the course of 4.5 years, 26 patients have been treated with methadone in the median dose of 3.0 mg/24 h p.o., for persisting breathlessness. Sixteen of them had been treated previously with an opioid (usually morphine) at the median dose of 7.0 mg/24 h (morphine oral daily dose equivalent). They were transferred to methadone, with the median dose of 3.0 mg/24 h orally (methadone oral daily dose equivalent), and the median morphine-to-methadone dose ratio was 2.5:1. All patients experienced a meaningful improvement in breathlessness intensity after methadone, by a median of 5 points (range 1-8) on the 0-10 numerical rating scale (NRS) in the whole group, and by 2 points (range 0-8) in those pretreated with other opioids, mainly morphine. Low-dose methadone can be considered an efficient alternative to morphine for reducing breathlessness in people experiencing neurotoxic effects or at risk of developing them following treatment with morphine.

The Use of Low-Dose Methadone as Add-On to Ongoing Opioid Treatment in Palliative Cancer Care-An Underrated Treatment?

The aim of this review is to summarize the current knowledge of low-dose methadone treatment in palliative cancer care. In Sweden, methadone is quite common in specialized palliative care, where almost a tenth of patients are prescribed this drug. Negative attitudes towards methadone do not seem to prevent it from being used for pain management, and by starting with low doses and then increasing slowly and gradually, methadone can apparently be introduced safely. It is still uncertain whether methadone has a better analgesic effect than other opioids. However, for pain relief in cancer patients with severe and complex cancer-related pain, NMDA receptor inhibition with methadone may, in selected cases, be an attractive alternative, especially in the form of low-dose supplements to other ongoing opioids. Due to long half-life and complex metabolism, the use of methadone requires an experienced physician and solid follow-up. Continuous administration of opioids, including low-dose methadone, has been proven effective and safe in reducing pain in dying patients without increasing the risk of confusion, regardless of age.

Transition From Full Mu Opioid Agonists to Buprenorphine in Opioid Dependent Patients-A Critical Review.

Methadone, a full opioid agonist at the mu-, kappa-, and delta-receptor, and buprenorphine, a partial agonist at the mu receptor, are first-line medications in opioid maintenance treatment. Transition from methadone to buprenorphine may precipitate withdrawal, and no accepted algorithm for this procedure has been developed. Current treatment strategies recommend transfer from methadone to buprenorphine predominantly in patients at low doses of methadone (30–40 mg/day). There are some reports indicating that transition from higher doses of methadone may be possible. A number of dosing strategies have been proposed to soften withdrawal symptoms and facilitate transfer including use of other opioids or medications and especially microdosing techniques for buprenorphine. The case series and studies available thus far are reviewed.

Biochemical Differences Between High and Low Dose Methadone Clients on Stable Maintenance Therapy

Biochemical Differences Between High and Low Dose Methadone Clients on Stable Maintenance Therapy

996Factors predicting retention among people accessing outpatient methadone maintenance therapy in Tshwane, South Africa

Abstract Background In South Africa, increasing illicit opioid use and associated health challenges can be managed with opioid substitution therapy (OST), like methadone, provided it is prescribed at the recommended dose and duration. The Community Oriented Substance Use Programme (COSUP) provides free methadone to patients with Opiod Use Disorder across Tshwane, South Africa on need-based criteria. Methods A retrospective cohort using secondary data of patients treated with methadone at eight COSUP sites. The factors associated with the retention of 575 participants for the period December 2016 to September 2018 were analysed. Results Participants on lower methadone doses had decreased odds of being retained (0 to 20mg: adjusted odds ratio (aOR) 0.25, p-value (p)=0.002, 95% Confidence Interval (CI) 0.10 - 0.61; 20 to 40mg: aOR 0.20, p &amp;lt; 0.001, 95% CI 0.08 - 0.49). Participants receiving free methadone had 3.75 the odds to be retained (p &amp;lt; 0.001, 95% CI 2.47 - 5.70). Inner-city participants had 5.19 the odds to be retained (p &amp;lt; 0.001, 95% CI 2.99 - 9.03). White participants had 3.39 the odds of being retained (p = 0.001, 95% CI 1.64 - 7.00). Injecting heroin users had 0.63 the odds of being retained (p = 0.032; 95% CI 0.41 - 0.96). Conclusions Methadone doses above 50mg, access to free methadone, accessing care within the inner-city and the white population group were positively associated with retention. Injecting drug use was negatively associated. Key messages Provision of free methadone at adequate doses can aid in retaining patients within an outpatient OST programme.

Perioperative adolescent serotonin syndrome secondary to methadone and fentanyl administration: A case report

Serotonin Syndrome (SS) is a serious toxidrome associated with significant morbidity when undiagnosed or improperly managed. We report a perioperative case of serotonin syndrome in an adolescent male on fluoxetine (selective serotonin reuptake inhibitor-SSRI) therapy secondary to an intraoperative combined opioid analgesic regiment. He received low dose methadone and fentanyl for induction for a LeFort osteotomy, the presumed trigger for his perioperative SS. This study demonstrates the essential need for anesthesiologists’ vigilance regarding identifying SS, risk factors of SS and implementation of immediate and effective management. Abbreviations: GAD: Generalized Anxiety Disorder; GPCR: G-protein Coupled Receptor; IV: Intravenous; MAOI: Monoamine Oxidase Inhibitor; MDD: Major Depressive Disorder; OR: Operating Room; PACU: Post-Anesthesia Care Unit; RAE: Right Angle Endotracheal; SERT: Serotonin Transporter; SNRI: Serotonin-Norepinephrine Reuptake Inhibitor; SS: Serotonin Syndrome; SSRI: Selective Serotonin Reuptake Inhibitor.

First-line methadone for cancer pain: titration time analysis.

Methadone is a low-cost, strong opioid that is increasingly used as a first-line treatment for pain in palliative care (PC). Its long and unpredictable half-life and slow elimination phase can make titration challenging. Evidence for titration modalities is scarce. To describe the titration phase of the treatment with low-dose first-line methadone and the use of methadone for breakthrough pain. Prospective study with strong opioid-naïve patients with moderate to severe cancer pain followed at a tertiary PC unit in Argentina. Starting methadone dose was 2.5-5 mg/day every 8, 12, or 24 h. Titration allowed daily dose increases from day 1, and prescription of oral methadone 2.5 mg every 2 h with a maximum of 3 rescue doses/day for breakthrough pain. Pain control, methadone stabilization dose, and adverse effects, among other variables, were daily assessed over the first 7 days (T0-T7). Sixty-two patients were included. Initial median (IQR) methadone dose was 5(2.5) mg/day. Pain intensity decreased from a median (IQR) of 8 (2.3) at T0 to 4 (2.3) at T1 and remained ≤ 4 until T7 (all p < 0.0001 compared to T0). Similar results were obtained through the categorical and tolerability scales for pain. Fifty patients (81%) reached pain control, 66% in the first 48 h. Methadone daily doses at T2 and T7 were higher than that at T0: 7.5 (3) and 6.7 (5.5) versus 5 (2.5), respectively (all p < 0.05). The opioid escalation index at T7 was 1.7%. The median (IQR) number of rescues, stabilization dose, and time for stabilization was 0 (1), 5(4.5) mg, and 3(2) days, respectively. Two patients were discontinued due to delirium. All other side effects were mild. First-line, low-dose methadone using rescue methadone resulted in a pronounced and rapid decrease in pain, with minimal need for titration and for breakthrough doses, and no evidence of accumulation or sedation by the end of the week.

The Use of Methadone in Pediatric Cancer Pain - A Retrospective Study from a Governmental Cancer Center in India.

Background:The management of cancer-related pain relies on access to opioids. When regular opioids are not tolerated, or are insufficient, methadone is an affordable and effective analgesic.Aim:The aim of the project was to describe the pattern of use and clinical experience of methadone in pediatric cancer pain at a governmental cancer hospital in Hyderabad, one of the four Indian cancer centers with permission to prescribe methadone.Methods:This was a retrospective study of medical records of all children, under the age of 18, who had been prescribed methadone from September 9, 2017, to November 19, 2019. Data on analgesic effect, prior and concomitant analgesic treatment, opioid side effects, and the handling of methadone were analyzed.Results:A total of 11 children were identified and studied. Methadone was introduced mainly when pain was uncontrolled by regular opioids. Initial daily doses ranged from 1 to 15 mg. The duration of treatment ranged from 7 to 307, with a median of 50 days in the nine patients where treatment exceeded one single dosage. Good analgesic effect was reported in 5/9 children, unchanged from previous analgesic treatment in three patients and without any effect in one child. No severe side effects were reported.Conclusion:Low-dose methadone in the treatment of pediatric cancer pain at a low-resource cancer center was safe and well tolerated by the patients, with long treatment durations. It was safely managed, administered with single to double daily dosages, hence easy for patients and family to handle, and an affordable treatment option.

Factors associated with early and later dropout from methadone maintenance treatment in specialist addiction clinics: a six-year cohort study using proportional hazards frailty models for recurrent treatment episodes

BackgroundRetention in methadone maintenance treatment (MMT) is associated with reduced illicit drug use, criminal activity, and mortality; however, many clients move in and out of MMT. This study aims to identify determinants of time to dropout of MMT across multiple treatment episodes in specialist addiction services in Ireland. MethodsCohort study of persons attending specialist addiction clinics between 2010 and 2015. MMT episodes were periods of continuous treatment if there were no interruptions to treatment lasting > 7days. Proportional hazards frailty models were used to assess factors associated with time to dropout from recurrent MMT episodes at 3 (90 days) and 12 months (91-365 days). MMT episodes were right- censored at time of death, transfer to prison or primary care, and study end. ResultsA total of 2,035 individuals experienced 4,969 MMT episodes, with 2,724 dropout events during the six-year follow-up. Factors associated with dropout at 3 months included low dose methadone (<60 mg/day) (HR = 1.49, 95% CI 1.29-1.73) and previous dropout (HR = 1.65, 95% CI 1.41-1.92). Adherence was protective (HR = 0.91, 95% CI 0.90-0.92). Dropout at 12 months was associated with low dose methadone (HR = 1.44, 95% CI 1.23-1.68), previous dropout (HR = 1.37, 95% CI 1.16-1.61), males (HR 1.26, 95% CI 1.06-1.50), benzodiazepines (HR = 1.22, 95% CI 1.03-1.45) and number of comorbidities (HR = 1.12, 95% CI 1.05-1.20); adherence was protective (HR = 0.86, 95% CI 0.84-0.87). ConclusionsClients with a previous history of treatment dropout and those on low dose methadone should be identified as high risk for both early and later dropout. Inversely, adherence to treatment, not missing methadone doses, is protective.

Is Maternal Methadone Dose Associated with the Severity of Neonatal Abstinence Syndrome?

The aim of the study is to assess the correlation between maternal methadone dose and severity of neonatal abstinence syndrome (NAS) in infants that required pharmacological treatment for NAS. This is a retrospective analysis of 574 infants ≥35 weeks' gestation exposed to methadone in utero, born between August 2006 and May 2018, and who required pharmacological therapy for NAS. Indicators of NAS severity (duration of morphine treatment, maximum morphine dose, use of phenobarbital, and length of hospitalization) were compared between infants exposed to high (≥200 mg), intermediate (100-199 mg), and low doses (<100 mg) of methadone. Logistic and linear regression models were used to adjust for the covariates. Median (interquartile range) duration of medical treatment with morphine was higher in infants exposed to higher doses of methadone (low dose 23 [14-37] days, intermediate dose 31 [18-45] days, and high dose 35 [20-48] days, p < 0.001). Higher methadone doses were also predictive of longer duration of hospitalization, higher maximum morphine dose, and increased likelihood of treatment with phenobarbital. The association between maternal methadone dose and the severity of NAS persisted in multivariable regression models. Infants exposed to higher methadone doses displayed more severe NAS, as indicated by longer durations of treatment, higher maximum morphine dose, longer duration of hospitalization, and increased likelihood of phenobarbital use. · Methadone maintenance therapy is used during pregnancy to control maternal withdrawal symptoms.. · Relationship between maternal methadone dose and severity of NAS is not adequately investigated.. · Increased doses of methadone during pregnancy correlate with increased severity of NAS..

Continuous subcutaneous infusion for pain control in dying patients: experiences from a tertiary palliative care center

BackgroundContinuous subcutaneous infusion (CSCI) via ambulatory infusion pump (AIP) is a valuable method of pain control in palliative care. When using CSCI, low-dose methadone as add-on to other opioids might be an option in complex pain situations. This study aimed to investigate the effects, and adverse effects, of CSCI for pain control in dying patients, with particular interest in methadone use.MethodsThis was an observational cohort study. Imminently dying patients with pain, admitted to specialized palliative inpatient wards and introduced on CSCI, were monitored daily by staff for symptoms (Integrated Palliative Care Outcome Scale - IPOS), sedation (Richmond Agitation and Sedation Scale – RASS), performance status (Eastern Cooperative Oncology Group - ECOG) and delirium (Confusion Assessment Method - CAM).ResultsNinety-three patients with a median survival of 4 days were included. Of the 47 patients who survived ≥3 days, the proportion of patients with severe/overwhelming pain decreased from 45 to 19% (p < 0.001) after starting CSCI, with only a moderate increase in morphine equivalent daily dose of opioids (MEDD). Alertness was marginally decreased (1 point on the 10-point RASS scale, p = 0.001), whereas performance status and prevalence of delirium, regardless of age, remained unchanged.Both patients with methadone as add-on (MET, n = 13) and patients with only other opioids (NMET, n = 34), improved in pain control (p < 0.05 and 0.001, respectively), despite that MET patients had higher pain scores at baseline (p < 0.05) and were on a higher MEDD (240 mg vs.133 mg). No serious adverse effects demanding treatment stop were reported.ConclusionsCSCI via AIP is an effective way to reduce pain in dying patients without increased adverse effects. Add-on methadone may be beneficial in patients with severe complex pain.

Low-dose methadone for refractory chronic migraine accompanied by medication-overuse headache: a prospective cohort study

ObjectivesA refractory chronic migraine (RCM) accompanied by medication-overuse headache (MOH) is an extremely disabling disease. Evidence suggests that in selected patients, chronic opioids may be a valuable therapeutic option for RCM. The aim of the present study was to evaluate the effectiveness and safety of prophylaxis with low-dose methadone (LDM) in patients affected by RCM with continuous headache and MOH.MethodsA prospective cohort study was performed between May 2012 and November 2015 at the Headache Center and Toxicology Unit of the Careggi University Hospital. Eligible patients were treated with prophylactic LDM and followed up for 12 months. Headache exacerbations, pain intensity, use of rescue medications, and occurrence of adverse drug reactions (ADRs) were recorded.ResultsThirty patients (24 females, median age 48 years) were enrolled. Nineteen (63%) patients dropped out, mainly because of early ADRs (n = 10), including nausea, vomiting, and constipation. At last available follow-up, LDM was associated with a significant decrease in the number of headache attacks/month (from a median of 45 (interquartile range 30–150) to 16 (5–30), p < 0.001), in pain intensity (from 8.5 (8–9) to 5 (3–6), p < 0.001), and in the number of rescue medications consumed per month (from 95 (34–240) to 15 (3–28), p < 0.001). No misuse or diversion cases were observed.ConclusionLDM could represent a valuable and effective option in selected patients affected by RCM with continuous headache and MOH, although the frequency of early ADRs poses major safety concerns. Randomized controlled trials are needed to confirm the efficacy and safety of LDM prophylaxis.