Clinical experience with transdermal and orally administered opioids in palliative care patients--a retrospective study

BACKGROUND: Transdermal fentanyl is a widely used opioid for the treatment of cancer pain. Simplicity of use and high patient compliance are the main advantages of this opioid. However, based on our clinical experience, transdermal fentanyl is often not efficacious in terminally ill palliative care patients. We thus retrospectively examined the pain management and need for opioid switching in cancer patients admitted to our palliative care unit. METHODS: Of 354 patients admitted to our palliative care unit from 2004 through 2005, 81 patients were pre-treated with transdermal fentanyl. Demographic and cancer-related data (diagnosis, symptoms, pain score on a numeric rating scale (NRS)), analgesic dose at admission and discharge were compared. Statistics: mean +/- SD, ANOVA, Wilcoxon's test was used for inter-group comparisons, significance P < 0.05, adjusted for multiple testing. Pain scores are given in median (range). RESULTS: Mean transdermal fentanyl dose at admission was 81.0 +/- 55.8 microg/h. In 79 patients transdermal fentanyl treatment was discontinued. In two patients, analgesic treatment according to WHO I provided sufficient pain relief. The other 77 patients were switched to other opioids: 33 patients to oral morphine and 44 to oral hydromorphone. In patients switched to morphine the dose at discharge (104.7 +/- 89.0 mg) was lower than at admission (165.5 mg morphine equivalence). In patients switched to hydromorphone the dose of 277.8 +/- 255.0 mg morphine equivalent was higher at discharge than at admission (218.2 +/- 131.4 mg morphine equivalence--considering an equianalgesic conversion ratio morphine: hydromorphone = 7.5: 1). Pain scores decreased significantly after opioid rotation (NRS at rest/on exertion: 4 (0-10)/7 (2-10) versus 1 (0-3)/2 (0-5); P < 0.001). CONCLUSIONS: In the patient group switched to morphine, sufficient pain relief was achieved by lower equianalgesic morphine doses, compared with the doses at admission. In the patient group switched to hydromorphone, higher equianalgesic morphine doses were needed at discharge, considering an equianalgesic conversion ratio of morphine: hydromorphone = 7.5: 1. Patients with far advanced cancer often suffer from sweating and cachexia, which may have negative effects on the absorption of transdermal fentanyl. Opioid switching to oral morphine or hydromorphone was well tolerated and proved to be an efficacious option for cancer pain treatment.     

Switching from morphine to methadone to improve analgesia and tolerability in cancer patients: a prospective study.

PURPOSE: To evaluate the clinical benefits of switching from morphine to oral methadone in patients who experience poor analgesia or adverse effects from morphine. PATIENTS AND METHODS: Fifty-two consecutive cancer patients receiving oral morphine but with uncontrolled pain and/or moderate to severe opioid adverse effects were switched to oral methadone administered every 8 hours using different dose ratios. Intensity of pain and adverse effects were assessed daily, and the symptom distress score (DS) was calculated before and after switching. RESULTS: Data were analyzed for 50 patients. Switching was considered effective in 80% of the patients; results were achieved in an average of 3.65 days. In the 10 patients who switched to methadone because of uncontrolled pain, a significant reduction in pain intensity (P <.005) and an average of a 33% increase in methadone doses necessary (P <.01) were found after an average of 3.5 days. DS significantly decreased from an average of 8.4 to 4.5 (P <.0005). In the 32 patients switching because of uncontrolled pain and morphine-related adverse effects, significant improvement was found in pain intensity (P <.0005), nausea and vomiting (P <.03), constipation (P <.001), and drowsiness (P <.01), but a significant increase in the methadone dose of an average of 20% (P <.004) was required. CONCLUSION: In most patients with cancer pain referred for poor pain control and/or adverse effects, switching to oral methadone is a valid therapeutic option. In the clinical setting of poor pain control, higher doses of methadone are necessary with respect to the equianalgesic calculated dose ratios previously published.     

Opioid switching from transdermal fentanyl to oral methadone in patients with cancer pain

BACKGROUND: Patients with cancer often are rotated from other opioids to methadone to improve the balance between analgesia and side effects. To the authors' knowledge, no clear guidelines currently exist for the safe and effective rotation from transdermal fentanyl to methadone. METHODS: The authors evaluated a protocol for switching opioid from transdermal fentanyl to oral methadone in 17 patients with cancer. Reasons for switching were uncontrolled pain (41.1% of patients) and neurotoxic side effects (58.9% of patients). Methadone was initiated 8-24 hours after fentanyl withdrawal, depending on the patient's previous opioid doses (from < 100 microg per hour to > 300 microg per hour). The starting methadone dose was calculated according to a 2-step conversion between transdermal fentanyl:oral morphine (1:100 ratio) and oral morphine:oral methadone (5:1 ratio or 10:1 ratio). The correlation between previous fentanyl dose and the final methadone dose or the fentanyl:methadone dose ratio was assessed by means of Pearson and Spearman correlation coefficients (r), respectively. A Friedman test was used to compare pain intensity before and after the switch and the use of daily rescue doses. RESULTS: Opioid rotation was fully or partially effective in 80% and 20%, respectively, of patients with somatic pain. Neuropathic pain was not affected by opioid switching. Delirium and myoclonus were reverted in 80% and 100% of patients, respectively, after opioid switching. A positive linear correlation was obtained between the fentanyl and methadone doses (Pearson r, 0.851). Previous fentanyl doses were not correlated with the final fentanyl:methadone dose ratios (Spearman r, - 0.327). CONCLUSIONS: The protocol studied provided a safe approach for switching from transdermal fentanyl to oral methadone, improving the balance between analgesia and side effects in patients with cancer.     

Rapid switching between transdermal fentanyl and methadone in cancer patients.

PURPOSE: The aim of this study was to examine the clinical effects of switching from transdermal (TTS) fentanyl to methadone, or vice versa, in patients with a poor response to the previous opioid. PATIENTS AND METHODS: A prospective study was carried out on 31 patients who switched from TTS fentanyl to oral methadone, or vice versa, because of poor opioid response. A fixed conversion ratio of fentanyl to methadone of 1:20 was started and assisted by rescue doses of opioids, and then doses were changed according to clinical response. Pain and symptom intensity, expressed as distress score, were recorded before switching doses of the two opioids and after subsequent doses. The number of changes of the daily doses, time to achieve stabilization, and hospital stay were also recorded. RESULTS: Eighteen patients were switched from TTS fentanyl to methadone, and seven patients were switched from methadone to TTS fentanyl. A significant decrease in pain and symptom intensity, expressed as symptom distress score, was found within 24 hours after switching took place in both directions. Unsuccessful switching occurred in six patients, who were subsequently treated with an alternative therapy. CONCLUSION: A rapid switching using an initial fixed ratio of fentanyl to methadone of 1:20 is an effective method to improve the balance between analgesia and adverse effects in cancer patients with poor response to the previous opioid. No relationship between the final opioid dose and the dose of the previous opioid has been found.     

Intravenous methadone in the management of chronic cancer pain: safe and effective starting doses when substituting methadone for fentanyl.

BACKGROUND: Patients often are rotated from other opioids to methadone when side effects occur before satisfactory analgesia is achieved. Various strategies have been proposed to estimate safe and effective starting doses of methadone when rotating from morphine and hydromorphone; however, there are no guidelines for estimating safe and effective starting doses of methadone when rotating from fentanyl. METHODS: The authors prospectively observed 18 consecutive patients experiencing chronic pain from cancer who underwent opioid rotation from intravenous patient-controlled analgesia (PCA) with fentanyl to intravenous PCA with methadone. Patients were switched from fentanyl to methadone because of uncontrolled pain associated with sedation or confusion. A conversion ratio of 25 microg/hour of fentanyl to 0.1 mg/hour of methadone was used to calculate the initial dose of methadone in all patients. RESULTS: Mean pain scores decreased from 8.1 to 4.8 on Day 1 after the switch and to 3.22 on Day 4 after the switch. Mean sedation scores were 1.5 before the switch and 0.44 and 0.16 on Days 1 and 4, respectively. Among the 6 patients who experienced confusion while on fentanyl before the switch, 5 improved within 2 days of the switch. None of the patients experienced toxicity from methadone. CONCLUSIONS: On the basis of this preliminary study, the authors suggest that when switching from intravenous fentanyl to methadone a conversion ratio of 25 microg/hour of fentanyl to 0.1 mg/hour of methadone may be safe and effective.     

Opioid analgesics in cancer pain: current practice and controversies

Pain is a complex somato psychic experience that requires a multimodality approach to treatment. Pharmacologically, pain in cancer can be divided into opioid non-responsive, opioid partially responsive, opioid responsive (but do not use opioids) and opioid responsive (do use opioids). Three concepts govern the use of analgesics in opioid responsive pains: 'by the mouth', 'by the clock' and 'by the ladder'. Adjuvant drugs may also be necessary. Morphine is the strong opioid of choice for cancer pain. In patients unable to take oral medication, morphine can be administered by suppository, by injection or peridurally. Useful alternative strong opioids include phenazocine, hydromorphone and buprenorphine. A number of controversial issues are discussed. These include the oral to parenteral potency ratio of morphine; the main site of metabolism of morphine; the relative merits of morphine and diamorphine; the risk of respiratory depression; the development of tolerance; and the risk of addiction.     

Opioid switching: a systematic and critical review

Cancer patients with pain may not respond to increasing doses of opioids because they develop adverse effects before achieving an acceptable analgesia, or the analgesic response is poor, despite a rapid dose escalation. Opioid switching may significantly improve the balance between analgesia and adverse effects. We conducted a systematic review of existing literature on opioid switching. According to available data, opioid switching results in clinical improvement in more than 50% of patients with chronic pain with poor response to one opioid. However, data are based on open studies or small case series. Reasons for switching may influence the dose of the alternative drug. Opioid conversion should not be a mere mathematical calculation, but just a part of a more comprehensive evaluation of pain, adverse effect intensity, comorbidities, and concomitant drugs. The process of reaching an optimal dose should be highly individualized, particularly when patients are switched from high doses of opioids, given the wide conversion ratios reported in literature.     

Opioid rotation for cancer pain: rationale and clinical aspects.

BACKGROUND: Some patients with cancer pain may develop uncontrolled adverse effects, including generalized myoclonus, delirium, nausea and emesis, or severe sedation before achieving adequate analgesia during opioid dose titration. Sequential therapeutic trials should be considered to determine the most favorable drug. METHODS: Recent literature was taken into account when reviewing the rationale and potential of opioid rotation. RESULTS: When aggressive attempts to prevent adverse effects fail, drug rotation should be considered, because sequential therapeutic trials can be useful in identifying the most favorable drug. Different mechanisms, including receptor activity, the asymmetry in cross-tolerance among different opioids, different opioid efficacies, and accumulation of toxic metabolites can explain the differences in analgesic or adverse effect responses among opioids in a clinical setting. CONCLUSIONS: When pain is relieved inadequately by opioid analgesics given in a dose that causes intolerable side effects despite routine measures to control them, treatment with the same opioid by an alternative route or with an alternative opioid administered by the same route should be considered. Opioid rotation may be useful in opening the therapeutic window and for establishing a more advantageous analgesia/toxicity relationship. By substituting opioids and using lower doses than expected according to the equivalency conversion tables, it is possible in the majority of cases to reduce or relieve the symptoms of opioid toxicity in those patients who were highly tolerant to previous opioids while improving analgesia and, as a consequence, the opioid responsiveness.     

Opioid switch to oral methadone in cancer pain

The occurrence of undesirable side effects due to opioids (delirium, confusion, myoclonus, nausea, emesis) is one of the major complications in the management of pain, especially in chronic cancer pain states. Methadone, as an alternative to morphine, has been proposed in the control of opioid-induced toxicity. Methadone is a synthetic opioid, with mu and delta receptor activity, associated with the capacity to inhibit N-methyl-D-aspartate receptors. Questions have arisen concerning its equianalgesic ratio since its rediscovery over the past few years and are certainly related to its receptor interactions. Aspects of its pharmacology, indications, and switching modalities are discussed here. Opioid rotation is a new tool in the management of cancer pain, deserving more attention.     

Oxycodone and pregabalin using transdermal fentanyl patch provided relief of symptoms for postherpetic neuropathic pain in a patient with non-small cell lung cancer

This paper presents a man in his 70's with non-small cell lung cancer (cT3N2M0, Stage III A) after chemoradiation therapy during follow-up visits. He was referred to the department of palliative care 1 month after the occurrence of herpes zoster, because of pain. Opioids (transdermal fentanyl patch and rapid-release oxycodone) were administered for his cancer pain previously. Additionally, gabapentin was given for neuropathic pain uncontrolled by opioids. However, this was replaced by pregabalin because he experienced somnolence. Although numbing improved remarkably with pregabalin, the pain was only slightly improved. The dose of rapid-release oxycodone was increased and controlled-release oxycodone was added. This provided for marked pain relief. We conclude that administration of pregabalin as an analgesic adjuvant, and oxycodone, which is an opioid, should be considered in the treatment of cancer patients without improvement of neuropathic pain from herpes zoster through use of the transdermal fentanyl patch.     

Clinical pharmacology and pharmacotherapy of opioid switching in cancer patients

Pain is one of the most common and often most feared symptoms in patients with cancer. Ongoing or progressive pain is physically debilitating and has a marked impact on quality of life. Since a third of the population will die from cancer, and of these, 80% will experience severe pain in their final year of life, effective treatment of cancer-related pain remains both a high priority and an ongoing challenge in clinical practice. Individuals with moderate to severe cancer-related pain require treatment with strong analgesics, namely opioids. There is evidence to support the therapeutic maneuver of opioid switching in clinical practice, but further evidence is needed to elucidate the underlying mechanisms for interindividual differences in response to different opioids. Large, robust clinical trials will be needed if clinical differences among side-effect profiles of different opioids are to be clearly demonstrated. This review discusses candidate genes, which contribute to opioid response; many other genes have also been implicated in "pain" from animal or human studies. In order to continue to evaluate the genetic contributions to both pain susceptibility and analgesic response, further candidate genes need to be considered. Good pain control remains a high priority for clinicians and patients, and there is much work to be done to further individualize analgesic therapy for patients with cancer.     

恶性肿瘤患者临终前的阿片类药物止痛回顾

目的:调查恶性肿瘤患者临终前的阿片类药物止痛治疗现状。方法:分析242例患者阿片类药物止痛的基本情况,比较不同性别、年龄及肿瘤原发灶的阿片止痛情况。结果:176例(72.73%)用阿片止痛,其中134例(76.14%)用美施康定,28例(15.91%)用多瑞吉,14例(7.95%)用弱阿片,无阿片过量引起的死亡。日平均吗啡口服剂量:男性(166.67mg)明显高于女性(107.66mg),年龄增大,用量逐渐减小,但无显著差异,不同原发灶的患者无显著差异。结论:止痛治疗合理、安全;男性止痛所需阿片量比女性大,年龄大的患者阿片用量较小,肿瘤原发灶与阿片止痛剂量无关。     

The opioid combination of transdermal fentanyl and sustained release morphine for refractory cancer pain--a case report

Transdermal fentanyl (TDF) has been increasingly administered for the management of cancer pain. Occasionally, some patients fail to obtain poor analgesic effects with its dose escalation. We discuss a case of a 44-year-old male diagnosed with lung cancer with back pain caused by bone metastasis. He was administered a TDF of 75 microg/hr with good pain relief on admission. With time, the dose escalation to 300 microg/hr induced neuroexcitatory adverse effects without pain improvement. The conversion to 150 microg/hr TDF and sustained-release oral morphine 360 mg/day provided effective pain control. This clinical phenomenon demonstrated a possible association with the development of opioid tolerance. Although several experimental approaches regarding partial opioid substitution or combining different opioids for better pain control were suggested, the basic studies of opioid tolerance do not justify conclusions. In this case, partial opioid rotation and opioid combination were beneficial approaches to pain management.     

Opioids for metastatic bone pain

Metastatic bone pain is characteristic of cancer pain. Satisfactory analgesic effects are achieved in more than 70% of patients with cancer pain who receive a combination of nonsteroidal anti-inflammatory drugs and opioids, according to the WHO therapeutic guidelines. Morphine, oxycodone, and fentanyl are commonly administered opioids. We found that the mean dose of oxycodone to achieve analgesic effects was 55 mg, and at doses of 相似文献   

Methadone versus morphine as a first-line strong opioid for cancer pain: a randomized, double-blind study.

PURPOSE: To compare the effectiveness and side effects of methadone and morphine as first-line treatment with opioids for cancer pain. PATIENTS AND METHODS: Patients in international palliative care clinics with pain requiring initiation of strong opioids were randomly assigned to receive methadone (7.5 mg orally every 12 hours and 5 mg every 4 hours as needed) or morphine (15 mg sustained release every 12 hours and 5 mg every 4 hours as needed). The study duration was 4 weeks. RESULTS: A total of 103 patients were randomly assigned to treatment (49 in the methadone group and 54 in the morphine group). The groups had similar baseline scores for pain, sedation, nausea, confusion, and constipation. Patients receiving methadone had more opioid-related drop-outs (11 of 49; 22%) than those receiving morphine (three of 54; 6%; P =.019). The opioid escalation index at days 14 and 28 was similar between the two groups. More than three fourths of patients in each group reported a 20% or more reduction in pain intensity by day 8. The proportion of patients with a 20% or more improvement in pain at 4 weeks in the methadone group was 0.49 (95% CI, 0.34 to 0.64) and was similar in the morphine group (0.56; 95% CI, 0.41 to 0.70). The rates of patient-reported global benefit were nearly identical to the pain response rates and did not differ between the treatment groups. CONCLUSION: Methadone did not produce superior analgesic efficiency or overall tolerability at 4 weeks compared with morphine as a first-line strong opioid for the treatment of cancer pain.     

Rectal methadone in cancer patients with pain: A preliminary clinical and pharmacokinetic study

Background: Cancer pain can be treated in most cases with oralanalgesics. However, during their clinical history, 53% to 70%of patients will need alternative routes of opioid administration.The rectal administration of opioids is a simple alternativeroute for many patients. There are no data in the literatureregarding the pharmacodynamics and pharmaco-kinetics of rectalmethadone Patients and methods: We evaluated the analgesia, toler-abilityand absorption profile of methadone hydrochloride in six opioid-naivecancer patients with pain. A blood sample was collected beforeadministration of a single dose of drug (10 mg) and then againafter fixed times. At these fixed times the patients were askedabout pain, nausea and drowsiness by means of a visual analoguescale of 0–100 mm (VAS) Results: Pain relief was statistically significant as earlyas 30 minutes and up to eight hours after methadone administration.None of the patients reported significant side effects. Theparmacokinetics of rectal methadone showed rapid and extensivedistribution phases followed by a slow elimination phase Conclusions: Rectal methadone can be considered an effectiveanalgesic therapy for patients with cancer pain for whom oraland/or parenteral opioids are not indicated or available cancer, methadone hydrochloride, pain, pharmacodynamics, pharmacokinetics, rectal route     

Methadone for treatment of cancer pain

Methadone is a unique μ opioid agonist, which also has δ receptor affinity and properties of N-methyl-D-aspartate receptor antagonism and monoamine reuptake inhibition. It is mainly used in the setting of uncontrolled pain or dose-limiting toxicity. Caution is advised when switching to methadone, especially from high doses of previous opioid, due to its variable conversion ratio and the potential for delayed toxicity due to its long half-life. Increasing evidence of risk also exists for a prolonged QT interval and torsades de pointes with very large doses of methadone. Methadone is likely safer when used at lower doses as a first-line opioid, but its potential as such has not received enough formal evaluation. Randomized controlled trials are needed to assess the effectiveness and safety of methadone compared with other opioids and to further evaluate its role in the treatment of neuropathic pain.     

盐酸羟考酮控释片阴道给药治疗癌性疼痛的临床研究

背景与目的：盐酸羟考酮控释片是治疗中重度癌性疼痛的强阿片类口服镇痛药,部分患者由于持续的恶心、呕吐、意识障碍或吞咽困难等,常使其口服应用受到限制。本研究目的是观察盐酸羟考酮控释片阴道给药方式治疗中重度癌性疼痛的疗效及不良反应,为口服药物困难的女性患者提供新选择。方法：36例不能口服药物中重度癌痛女性患者采用盐酸羟考酮控释片阴道给药方式治疗,以往未使用阿片类止痛药物者,初始盐酸羟考酮控释片剂量为10mg,每12h用药一次,剂量滴定参考口服给药方法：对凶不能继续口服盐酸羟考酮控释片而改用阴道给药方式者,继续原来剂量阴道给药。结果：36例患者中完全缓解6例,明显缓解20例,中度缓解和轻度缓解各4例,未缓解2例;中度以上疼痛缓解率为83．3％。中位起效时间为49min;中位镇痛时间为13．8h。主要不良反应为阴道烧灼感（9例,25．0％）,无因不良反应而中止治疗者。结论：盐酸羟考酮控释片阴道给药方式安全、有效、方便,在口服药物困难的女性患者是一种可选择的给药方式。     

Controversies in pharmacotherapy of pain management

Since the establishment of the WHO three-step ladder for management of cancer pain, several controversies have arisen, which are partly due to new drug development, reformulations of older analgesics, and technological advancements. As a result, clinicians need clarification of several questions. Is morphine the opioid of choice for moderate to severe pain in cancer? Should combinations of opioids be used? When should spinal opioids be used to treat pain in cancer? What are the appropriate opioid doses for breakthrough pain? Should selective cyclo-oxygenase (COX) 2 inhibitors be used? What is the best tactic to treat neuropathic pain, and what first-line adjuvant analgesic should be used? And do bisphosphonates relieve bone pain in cancers other than breast cancer and myeloma? This review addresses these questions.     

盐酸羟考酮缓释片治疗中重度癌痛60例临床观察

目的：观察盐酸羟考酮缓释片治疗中重度癌痛患者的镇痛效果和安全性.方法：应用盐酸羟考酮缓释片治疗60例中重度癌痛患者,评价镇痛效果、生活质量、不良反应.对于初次使用阿片类药物的患者,滴定方法：起始剂量为10mg,给药1小时后评估镇痛效果,反复滴定,直至NRS 0-3分,维持此剂量,每12小时口服1次.出现爆发痛,予以前日盐酸羟考酮缓释片总固定量的10％-20％.阿片耐受的患者,则将前24小时的累积剂量换算成短效阿片（每4小时量）,在此基础上再增加50％-100％剂量.结果：60例中重度癌痛患者口服盐酸羟考酮缓释片剂量在20-760mg/天之间,平均剂量154.3mg/天,滴定达有效剂量的平均天数为2.5天.疼痛总缓解率95.0％,其中完全缓解13例,部分缓解44例.中、重度癌痛患者生活质量总有效率分别为92.9％、93.8％.不良反应主要为便秘、恶心、呕吐、头晕.结论：盐酸羟考酮缓释片治疗中重度癌痛患者疗效稳定,不良反应少,安全性高.