Long term methadone for chronic pain: a pilot study of pharmacokinetic aspects.

Methadone is used as an alternative opioid when first line opioids fail to provide adequate pain control. Highly variable morphine:methadone dose ratios make switching challenging and little is known about the pharmacokinetics of long lasting methadone treatment for pain. Twelve patients treated with morphine for chronic non-malignant pain were switched to methadone. Seven of these patients continued with methadone throughout the nine months study period and only minor dose adjustments were performed. Serum concentrations of morphine, methadone and their metabolites were measured at baseline, day one and two, after dose titration and one week, five weeks, three months and nine months after the end of dose titration. Serum concentrations of methadone and its metabolite EDDP did not change significantly from the end of dose titration and during the nine months (repeated measures ANOVA: p=0.88 and p=0.06). Very low correlation between dose ratios and serum concentration ratios between morphine and methadone was observed. Large interindividual differences in serum concentrations and metabolism were observed. Our findings contradict that autoinduction of methadone metabolism takes place during long term treatment and supports that a 3-day opioid switch from morphine to methadone followed by a one week titration seems pharmacologically sound.     

Sustained‐release oral morphine versus transdermal fentanyl and oral methadone in cancer pain management

Purpose: The aim of this study was to compare the analgesic and adverse effects, doses, as well as cost of opioid drugs, supportive drug therapy and other analgesic drugs in patients treated with oral sustained‐release morphine, transdermal fentanyl, and oral methadone. Patients and methods: One hundred and eight cancer patients, no longer responsive to opioids for moderate pain, were selected to randomly receive initial daily doses of 60mg of oral sustained‐release morphine, 15mg of oral methadone, or 0.6mg (25μg/h) of transdermal fentanyl. Oral morphine was used as breakthrough pain medication during opioid titration. Opioid doses, pain intensity, adverse effects, symptomatic drugs, were recorded at week intervals for 4weeks. Costs of opioid therapy, supportive drugs, and other analgesic drugs were also evaluated. Results: Seventy patients completed the 4weeks period of study. Five, five, and four patients, treated with oral morphine, transdermal fentanyl, and oral methadone, respectively, required opioid switching. No differences in pain and symptom intensity were observed. Opioid escalation index was significantly lower in patients receiving methadone (p<0.0001), although requiring up and down changes in doses. At the doses used, methadone was significantly less expensive (p<0.0001), while the use and costs of supportive drugs and other analgesics were similar in the three groups. No relevant differences in adverse effects were observed among the groups during either the titration phase and chronic treatment. Conclusion: All the three opioids used as first‐line therapy were effective, well tolerated, and required similar amounts of symptomatic drugs or co‐analgesics. Methadone was significantly less expensive, but required more changes, up and down, of the doses, suggesting that dose titration of this drug requires major clinical expertise.     

Pharmacological consequences of long-term morphine treatment in patients with cancer and chronic non-malignant pain.

BACKGROUND: In patients with pain of malignant origin morphine may be administered in high and often increasing doses during extended periods of time. In patients with chronic pain of non-malignant origin morphine may be an important remedy, and in these cases the goal is to keep the morphine dose stable. The pharmacokinetic as well as the pharmacodynamic consequences of long-term morphine treatment with special reference to the two most important metabolites of morphine morphine-6-glucuronide (M-6-G) and morphine-3-glucuronide (M-3-G) remain to be settled. METHODS: Assessments for pain, sedation and other morphine induced side effects were made several times for 19 cancer patients treated with changing doses of oral sustained release (SR) morphine and twice for 17 non-cancer patients treated with stable doses of SR morphine. Blood samples were obtained simultaneously and analysed for contents of morphine, M-3-G and M-6-G by high-performance liquid chromatography (HPLC). RESULTS: Significant correlations were found between the daily dose of SR morphine and plasma morphine (r = 0.469, p < 0.01), plasma M-6-G (r = 0.677, p < 0.01), and plasma M-3-G ((r = 0.827, p < 0.01), in the cancer patient group, but only between the daily dose of SR morphine and plasma M-3-G (0.662, p < 0.01) and plasma M-6-G (0.571, p < 0.01) in the non-cancer patient group. Normalised M-3-G/M and M-6-G/M ratios for the cancer patient group were independent of duration of treatment and daily dose of SR morphine. Likewise in the non-cancer patient group duration of treatment did not influence the metabolite ratios. Correlations between pain score and plasma morphine, M-6-G and M-6-G/M were weak in the cancer patient as well as in the non-cancer patient group making it impossible to draw any conclusion regarding the potential contributory analgesic effect of M-6-G. Dryness of the mouth was the most frequent adverse effect reported in the non-cancer as well as the cancer patient group. In the latter group patients complaining of dryness of the mouth had significantly higher plasma morphine and M-6-G concentrations than patients who did not suffer from this side effect. This difference persisted (or was close to significance) when excluding patients receiving antidepressants. CONCLUSION: In the cancer patient group neither dose nor treatment period seems to influence morphine glucuronidation. Likewise in the non-cancer patient group receiving stable doses of morphine duration of treatment does not seem to influence morphine glucuronidation. Dryness of the mouth was positively correlated to high plasma concentrations of morphine and M-6-G.     

Opioid dependence and addiction during opioid treatment of chronic pain

Throughout the long history of opioid drug use by humans, it has been known that opioids are powerful analgesics, but they can cause addiction. It has also been observed, and is now substantiated by multiple reports and studies, that during opioid treatment of severe and short-term pain, addiction arises only rarely. However, when opioids are extended to patients with chronic pain, and therapeutic opioid use is not confined to patients with severe and short-lived pain, compulsive opioid seeking and addiction arising directly from opioid treatment of pain become more visible. Although the epidemiological evidence base currently available is rudimentary, it appears that problematic opioid use arises in some fraction of opioid-treated chronic pain patients, and that problematic behaviors and addiction are problems that need to be addressed. Since the potentially devastating effects of addiction can substantially offset the benefits of opioid pain relief, it seems timely to reexamine addiction mechanisms and their relevance to the practice of long-term opioid treatment for pain. This article reviews the neurobiological and genetic basis of addiction, its terminology and diagnosis, the evidence on addiction rates during opioid treatment of chronic pain and the implications of biological mechanisms in formulating rational opioid treatment regimes.     

CSF and plasma morphine concentrations in cancer patients during chronic epidural morphine therapy and its relation to pain relief

Seventeen patients with advanced cancer pain, treated with chronic epidural morphine, were studied. Minimum plasma and CSF morphine concentrations (Css_min) were determined at pharmacokinetic steady state. A linear relationship was found between epidural morphine dose and concentrations obtained in plasma (r = 0.92) as well as CSF (r = 0.90). The line for best fit was much steeper for CSF than for plasma. The CSF/plasma concentration gradient of morphine at Css_min was 132 ± 31 (mean ± S.E.M.). Large interindividual variations of morphine concentrations in CSF were found. It is suggested that the variations are due to substantial differences in transdural morphine diffusion between individuals. No correlation was found between pain relief, evaluated with a visual analog scale, and CSF morphine concentrations at pharmacokinetic steady state, when calculated in 9 patients. Mean duration of treatment was 104 days (range 14–366) and the daily dose was increased from 18 ± 2 to 87 ± 31 mg/day (mean ± S.E.M.). A total of 39 epidural catheters were inserted in 14 patients. The catheters were patent for 2–223 days with a mean of 38 days. When re-examined later during treatment, 2 out of 8 patients demonstrated decreased CSF morphine concentrations in spite of increased doses given. One patient with extremely high dose demand is reported on separately and data supporting the concept of a combined spinal and systemic brain morphine effect in such cases are presented. Side effects were not a major problem but the possibility of infectious complications should be considered during chronic epidural morphine therapy.     

A randomized study on oral administration of morphine and methadone in the treatment of cancer pain

Over a period of 14 days, 54 patients with incurable chronic cancet pain were observed: 27 were randomized for treatment with morphine per os and 27 with methadone per os. Data regarding daily dosage, analgesic effects, hours of sleep, hours standing, performance status (PS) and side effects were collected during both treatments. The results show overlapping analgesic efficacy and side effects for both drugs, and confirm the hypothesis that lower doses of methadone are required than morphine. In the treatment with methadone, the initial average dose was 18 mg, and this dose was maintained throughout the entire period, whereas the initial average daily dose of morphine was 72.74 mg (±39.25), and the final average daily dose was 119.40 mg (±79.1). The findings in this study show that methadone is a valid alternative to morphine in cancer pain treatment even though, as a result of its pharmaceutical charcteristics, it requires a differnt titration for the patient.     

Treatment of pain in chronic bowel subobstruction with self-administration of methadone

 Chronic treatment with opioids in cancer patients with chronic intestinal obstruction is hazardous, as uncontrolled constipation may result in definitive bowel obstruction. Intermittent use of opioids adjusted for fluctuating pain levels may enable patients to take the lowest opioid doses that will have sufficient effect, with a consequently lower risk of intestinal side effects. Methadone has many pharmacokinetic characteristics that fit it for use in this clinical situation. In two patients with recurrent episodes of bowel obstruction, methadone used at low doses and at flexible intervals regulated by the patients according to their pain level avoided the occurrence of new episodes of intestinal obstruction. Oral patient-controlled analgesia with methadone may be a simple, safe and cheap method of treating patients with pain associated with subtotal intestinal obstruction.     

Methadone treatment of chronic non-malignant pain and opioid dependence--a long-term follow-up.

Iatrogenic opioid addiction among chronic pain patients was the initiative for starting a methadone programme for pain patients at the University Hospital of Uppsala. The aims were to improve pain relief and quality of life in pain patients with problematic opioid use and to investigate background factors explaining problems with opioid use. METHODS: Records of all 60 patients included in the methadone programme 1994-2002 were studied. An interview was done after a mean of 34 months of methadone treatment regarding pain relief, quality of life and side effects on 48 patients. RESULTS: Titration of oral methadone mixture in daily doses ranging from 10 to 350 mg (mean 99.5 mg) was done on all patients. Background factors were low back and musculoskeletal pain in 40%, psychiatric disease in 68%, and substance use disorder in 32% of the patients. Before methadone treatment all patients were on sick leave. After treatment five patients returned to work. Ten patients failed treatment, 4 due to intractable nausea, 4 to drug diversion, 1 because of methadone related arrhythmia and 1 because of insufficient analgesia. Pain relief was rated good by 75% and moderate by 25% of the patients. Global quality of life was rated at mean of 50(0-100), which favourably compares with Swedish chronic pain patients mean 33(0-100). CONCLUSION: A structured methadone programme can be used for treating chronic pain patients with opioid dependence improving pain relief and quality of life. However, side effects and serious adverse events may limit the beneficial effects of the method.     

美沙酮维持治疗者滥用甲基苯丙胺的因素分析

目的 探讨美沙酮维持治疗(methadone maintenance treatment,MMT)者滥用甲基苯丙胺的影响因素。 方法 选取2013年1月-2016年6月在MMT门诊接受治疗的255例患者为调查对象,自拟调查问卷统计社会学特征、对甲基苯丙胺的认知情况、MMT治疗情况,进行单因素及多因素Logistic回归分析。 结果 255例MMT患者中,甲基苯丙胺尿检阳性者28例,占11.0%,单因素分析结果表明不同性别、年龄、居住方式、对甲基苯丙胺的了解情况、甲基苯丙胺对性行为影响的认知、近3个月是否吸食毒品的患者,其甲基苯丙胺尿检阳性率存在统计学差异,多因素Logistic回归分析结果表明年龄(OR=2.190)、甲基苯丙胺对性行为影响的认知(OR=1.237)及近3个月吸食毒品(OR=2.876)是造成甲基苯丙胺滥用的危险因素。 结论 针对MMT患者滥用甲基苯丙胺的危险因素,应当加强教育,以减少甲基苯丙胺的使用,预防艾滋病感染。     

Pharmaceutical treatment patterns for patients with a diagnosis related to chronic pain initiating a slow-release strong opioid treatment in Sweden

Slow-release strong opioids (SRSO) are indicated in patients with severe chronic pain. Side effects, lack of efficacy and risk of dependency limit their use in clinical practice.     

音乐疗法辅助吗啡减轻肿瘤患者疼痛的效果

目的 观察音乐疗法辅助吗啡减轻患者疼痛的程度,以降低药物需求量.方法 将52例肿瘤中度疼痛以上患者随机分为实验组（30例）和对照组（22例）,在应用止痛药物前,记录疼痛级别和用药情况,在用药后实验组通过MP3耳机听舒缓音乐,对照组则单纯以药物治疗.结果 实验组疼痛缓解程度和吗啡用药剂量均低于对照组,实验组有效率90%,对照组有效率77.3%,差异有统计学意义（P＜0.05）.结论 音乐疗法辅助吗啡在治疗肿瘤患者疼痛中,能使疼痛级别降低及吗啡用量减少.     

Exploring beliefs and practice of opioid prescribing for persistent non-cancer pain by general practitioners.

Persistent non-cancer pain is a common reason for consultation in primary care but treatment options, including non-opioid analgesics, are limited, and neither strong evidence nor established guidelines address when and how primary care doctors should prescribe opioid analgesics for persistent non-cancer pain. The aim of this study was to investigate associations between doctors' prescribing patterns for persistent non-cancer pain in primary care and their personal and practice characteristics and beliefs about appropriateness and risks of opioids. A pilot survey sampled beliefs concerning the need for and risks of opioid prescribing for persistent non-cancer pain among volunteers from primary care practices and postgraduate educational events, using a self-report questionnaire, and related these beliefs to their reported opioid prescribing. One quarter of the sample prescribed no opioids for persistent non-cancer pain. Prescribing opioids was predicted by moderate belief in the appropriateness of opioids within certain constraints, and to a lesser extent by younger age. While some beliefs distinguished prescribers from non-prescribers, predicting non-prescribing was poor. Both prescribers and non-prescribers expressed concern about the risks of opioids. In addition, most primary care doctors were dissatisfied with their training on pain; few had prescribing guidelines; and neither training nor guidelines influenced prescribing. In conclusion, whether or not GPs prescribe opioids for persistent non-cancer pain is mainly determined by their personal beliefs about appropriateness of opioids for this problem.     

癌性疼痛患者应用吗啡的影响因素及分析

目的 探讨癌性疼痛患者使用吗啡的影响因素,为临床护士实施护理措施提供帮助.方法 2010年4月1日-2010年10月31日对收住上海中医药大学附属普陀医院肿瘤科未服用吗啡的癌性疼痛患者87例进行调查,内容包括一般情况和影响吗啡应用的因素.结果 影响吗啡应用的主要因素:63.2%患者担心吗啡成瘾性;60.9%患者担心吗啡耐药性、剂量会增加;57.4%患者担心吗啡的不良反应难以忍受;44.8%患者认为疼痛一定会有,无法治疗,只能忍受;34.5%患者认为病情还未发展到需服用吗啡的程度;28.7%患者担心过早使用吗啡,今后疼痛加重则无法控制疼痛;21.8%患者担心吗啡价格昂贵、负担不起等.结论 根据影响患者吗啡应用的主要因素,制订适合患者需求的健康教育,提高癌性疼痛患者正确应用吗啡的认知状态,有助于癌症患者正确使用吗啡,减少不良反应的发生,提高癌症患者的生活质量.     

A population-based study on chronic pain and the use of opioids in Portugal

Although increasing doubts exist regarding the long-term effectiveness and safety of opioids in patients with chronic pain (CP), most guidelines still recognize opioids as an option in effective management of CP. We aimed to describe the prevalence and factors associated with opioid use in subjects with CP in Portugal and to evaluate satisfaction and self-assessed treatment effectiveness. A nationwide study was conducted in a representative sample of the adult Portuguese population. The 5094 participants were selected using random digit dialing and estimates were adequately weighted for the population. The prevalence of opioid use by subjects with CP was 4.37% (95% confidence interval [CI] 3.4–5.5); and in subjects experiencing CP with and without cancer, it was 10.13% and 4.24%, respectively. Use of strong opioids was reported by only 0.17% of CP subjects. Sex, pain severity and symptoms of depression and anxiety were significantly associated with opioid use; however, in multivariate modeling, only pain-related disability remained significant. No significant differences among users and nonusers of opioids were observed regarding treatment satisfaction and self-assessed effectiveness. Although extremely high rates of use of opioids exist in a few countries, it should not be seen as a ubiquitous problem. Indeed, we showed that in Portugal, as in many other regions in the world, opioids are used much less frequently than in those few countries. Moreover, we did not find significant differences among users and nonusers of opioids regarding satisfaction and self-assessed effectiveness, eventually showing the results to be in line with reports that show doubt about opioids’ effectiveness. Further research and particular attention to and continuous monitoring of the trends of use and abuse of opioids worldwide are recommended.     

Emergency Departments Treating Veterans for Suicide: Ensuring Quality Care for Veterans Outside of Department of Veterans Affairs Health Care Facilities

IntroductionVeterans die by suicide at higher rates than nonveterans. Given that the emergency department is often the first point of entry to healthcare following a suicide attempt, it would be beneficial for community providers to have knowledge of the characteristics, medical issues, and effective treatments most often associated with those having served in the military to ensure guideline concordant and quality suicide care. This study aimed to identify assessment and referral practices of emergency departments at rural community hospitals related to care for suicidal veterans and explore the feasibility and acceptability of identifying veterans in need of postdischarge aftercare.MethodsThis qualitative exploratory study involved content analysis of semistructured interviews. Ten emergency clinicians from 5 rural Arkansas counties with high suicide rates were interviewed about their experiences working with suicidal patients within the emergency department and perceptions of assessment, management, and referral practices.ResultsAlthough most of the emergency departments had a process for assessing for suicide risk, emergency clinicians did not always feel confident in their knowledge of assessing and caring for suicidal patients. Military history was not included in assessment, treatment, or aftercare planning, nor were brief interventions such as safety planning or lethal means safety education provided.DiscussionBest practices for suicide assessment and management of veterans exist; however, challenges specific to the emergency department regarding staff training and engaging the community to effectively link at-risk veterans to needed care hinder implementation. Veteran-inclusive assessment and intervention practices could enhance the quality of care provided in community emergency departments.     

A phase III placebo- and oxycodone-controlled study of tanezumab in adults with osteoarthritis pain of the hip or knee

Tanezumab is a humanized monoclonal antinerve growth factor antibody in development for treatment of chronic pain. In a phase III, placebo- and active-controlled study, we investigated the efficacy and safety of tanezumab for osteoarthritis (OA) hip or knee pain. Patients (N = 610) received up to 2 doses of intravenous tanezumab (5 or 10 mg in 8-week intervals), controlled-release oral oxycodone (10 to 40 mg every 12 hours), or placebo. The primary endpoint was mean change from baseline to week 8 in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain score for tanezumab versus placebo and oxycodone. Secondary endpoints included change from baseline in WOMAC Physical Function and Stiffness scores, Patient’s Global Assessment (PGA) of OA, and patient response, defined as ?30%, ?50%, ?70%, and ?90% improvement from baseline in WOMAC Pain score. Tolerability and safety also were assessed. Both tanezumab groups demonstrated significant improvements in WOMAC Pain score versus placebo (P < .001) and oxycodone (P ? .018). Tanezumab also provided significant improvements versus placebo and oxycodone for WOMAC Physical Function and Stiffness scores and PGA of OA (P ? .002 for all) at week 8. For all analyses, oxycodone did not differ from placebo. Adverse event frequency was higher with oxycodone (63.3%) than tanezumab (40.7% to 44.7%) or placebo (35.5%); serious adverse event frequency was similar among treatments. The adverse event profile for tanezumab was similar to previous tanezumab studies. Results indicate that tanezumab is efficacious in the treatment of OA pain; no new safety signals were identified.     

Comparison of intranasal ketamine versus IV morphine in reducing pain in patients with renal colic

Background

Various drugs have been used to relieve abdominal pain in patients with renal colic. Ketamine is a popular choice as an analgesic.