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.     

Efficacy and tolerability of cancer pain management with controlled-release oxycodone tablets in opioid-naive cancer pain patients, starting with 5 mg tablets

BACKGROUND: We conducted an open-label, dose titration study to assess the efficacy and tolerability of controlled-release oxycodone in the therapy of cancer pain management, starting with a newly developed 5 mg tablet every 12 h. METHODS: Twenty-two Japanese cancer patients with pain who had not been taking opioid analgesics over the previous 2 weeks were enrolled. The length of time and the dose needed to attain stable and adequate pain control were evaluated in addition to the assessment of analgesic efficacy and safety during the study period. RESULTS: Eighteen patients in the efficacy population (18 out of 20, 90%) attained stable, adequate pain control. Two-thirds of the patients attained stable, adequate pain control without any dose titration. The mean length of time was 1.2 days. In these patients, the pain was significantly reduced in intensity, even at 1 h after the initial dose intake. Fifteen patients (68%) reported at least one side effect, but only one patient had to withdraw from the study because of a side effect. CONCLUSION: The results suggest that controlled-release oxycodone tablets offered stable and adequate pain control within a short period of time in most Japanese cancer patients who have not been taking opioid analgesics, and could be effectively titrated against pain from a starting dose of 5 mg every 12 h. This indicates that a lower strength controlled-release oxycodone formulation may make it possible to start and titrate the dose more appropriately and carefully in patients who are sensitive to opioid analgesics.     

口服控释吗啡交替为芬太尼透皮贴剂的疗效分析

目的评价晚期癌痛患者由口服控释吗啡转换为芬太尼透皮贴剂止痛的疗效与不良反应。方法 40例口服控释吗啡镇痛不满意的晚期癌痛患者,交替为芬太尼透皮贴剂,吗啡与芬太尼贴剂的剂量换算比为100∶1。采用0～10视觉模拟评分法评价疼痛强度,评分降低≥2表示疼痛缓解有临床显著性差异;不良反应评估分为4级:无不良反应(0)、轻度(1)、中度(2)或重度(3)。结果药物交替后疼痛强度明显降低,转换前平均疼痛评分为5.7,转换后7 d降至3.4。发生至少一种不良反应的患者转换前为37例(92.5%),转换后降至25例(62.5%)。结论将口服控释吗啡交替为芬太尼透皮贴剂是一种安全有效的镇痛策略。     

Morphine or oxycodone in cancer pain?

Oxycodone is an opioid analgesic that closely resembles morphine. Oxymorphone, the active metabolite of oxycodone, is formed in a reaction catalyzed by CYP2D6, which is under polymorphic genetic control. The role of oxymorphone in the analgesic effect of oxycodone is not yet clear. In this study, controlled-release (CR) oxycodone and morphine were examined in cancer pain. CR oxycodone and morphine were administered to 45 adult patients with stable pain for 3-6 days after open-label titration in a randomized, double-blind, cross-over trial. Twenty patients were evaluable. Both opioids provided adequate analgesia. The variation in plasma morphine concentrations was higher than that of oxycodone, consistent with the lower bioavailability of morphine. Liver dysfunction affected selectively either oxycodone or morphine metabolism. Three patients with markedly aberrant plasma opioid concentrations are presented. Significant individual variation in morphine and oxycodone metabolism may account for abnormal responses during treatment of chronic cancer pain.     

Three-day-type transdermal fentanyl patch conversion by rapid titration method with short-acting oral oxycodone for cancer pain

This study compared the efficacy and safety of a 3-day-type transdermal fentanyl patch conversion by the rapid titration method to short-acting oral oxycodone for cancer pain.We evaluated seven hospitalized cancer patients who had moderate to severe cancer pain.Pain intensity was rated using an 11-point(0-10)numerical rating scale(NRS).All 7 patients initially reported their pain intensity at rest as NRS≥4 during treatment by Non-Steroidal Anti-Inflammatory Drugs(NSAIDs).Short - acting oral oxycodone(OxiNorm?)5 mg was administered to all patients.One hour after short-acting oral oxycodone was administered, pain assessment was carried out using NRS by the author.Short -acting oral oxycodone was administered four times a day periodically, and as a rescue dose.If the total daily dose of short-acting oral oxycodone was stable for 2 days, we switched to the 3-day-type transdermal fentanyl patch.The optimal dosage of the 3-day-type transdermal fentanyl patch was determined by titration of short-acting oral oxycodone.All 7 patients reported mild levels(NRS≤2)of cancer pain for 2 days.No serious side effects were reported.The 3-day-type transdermal fentanyl patch conversion by the rapid titration method with short-acting oral oxycodone can be accomplished safely and effectively for patients with moderate cancer pain.     

Oxycodone: a pharmacological and clinical review

Oxycodone is a semi-synthetic opioid with an agonist activity on mu, kappa and delta receptors. Equivalence with regard to morphine is 1:2. Its effect commences one hour after administration and lasts for 12 h in the controlled-release formulation. Plasma half-life is 3–5 h (half that of morphine) and stable plasma levels are reached within 24 h (2–7 days for morphine). Oral bioavailability ranges from 60 to 87%, and plasma protein binding is 45%. Most of the drug is metabolised in the liver, while the rest is excreted by the kidney along with its metabolites. The two main metabolites are oxymorphone — which is also a very potent analgesic — and noroxycodone, a weak analgesic. Oxycodone metabolism is more predictable than that of morphine, and therefore titration is easier. Oxycodone has the same mechanism of action as other opioids: binding to a receptor, inhibition of adenylyl-cyclase and hyperpolarisation of neurons, and decreased excitability. These mechanisms also play a part in the onset of dependence and tolerance. The clinical efficacy of oxycodone is similar to that of morphine, with a ratio of 1/1.5–2 for the treatment of cancer pain. Long-term administration may be associated with less toxicity in comparison with morphine. In the future, both opioids could be used simultaneously at low doses to reduce toxicity. It does not appear that there are any differences between immediate and slow-release oxycodone, except their half-life is 3–4 h, and 12 h, respectively. In Spain, controlled-release oxycodone (OxyContin®) is marketed as 10-, 20-, 40-or 80-mg tablets for b.i.d. administration. Tablets must be taken whole and must not be broken, chewed or crushed. There is no food interference. The initial dose is 10 mg b.i.d. for new treatments and no dose reduction is needed in the elderly or in cases of moderate hepatic or renal failure. Immediate-release oxycodone (OxyNorm®) is also available in capsules and oral solution. Side effects are those common to opioids: mainly nausea, constipation and drowsiness. Vomiting, pruritus and dizziness are less common. The intensity of these side effects tends to decrease over the course of time. Oxycodone causes somewhat less nausea, hallucinations and pruritus than morphine.     

Patient-controlled analgesia with oral methadone in cancer pain: Preliminary report

BACKGROUND:: Methadone is a very useful drug in cancer pain because of itslow cost, lack of active metabolites, high oral availability,and the rapid onset of its analgesic effect. It seems to bewell tolerated in patients with difficult pain syndromes whoare receiving high doses of opioids, and it may deter the developmentof tolerance, but a high individual variation in terminal eliminationhalf-life can result in different rates and extents of drugaccumulation. For this reason, oral patient-controlled analgesiawith methadone was used in 24 advanced-disease patients withpain. PATIENTS AND METHODS:: A regimen of self-administered oral methadone at fixed dosesand flexible patient-controlled dosage intervals to achieveadequate analgesia, while avoiding toxic effects of methadoneaccumulation, was used in 24 patients requiring opioid therapy.After a priming period of three days with fixed doses of 3–5mg three times a day for naïve patients and 50% of themorphine equivalent of methadone in patients switched from morphine,patients and relatives were instructed to maintain the night-timedose and to administer a second dose when the pain recurred.When than four doses of methadone a day were used, an increaseof the dosage was prescribed. Continuous pain assessment andmonitoring of symptoms were offered. RESULTS:: The majority of patients achieved good pain relief until death,and three were switched to very low doses of subcutaneous morphinein their final days. The methadone escalation index was about2% a day, with a mean dosage increase of 0.3 mg a day for anaverage of 60 days of treatment at doses ranging from 9 to 80rug. The plasma concentration in 14 patients ranged from 0.013to 0.273 mcg/ml with dosages of 20–80 mg during chronictreatment. A mean of 2.4 doses a day was reported, includingthe fixed night-time dose. The extent of side effects was consideredacceptable. CONCLUSION:: Patient-administered analgesia with oral methadone appears tobe a simple, cheap and relatively safe technique for controllingcancer pain, permitting individualization by the patient him-or herself and avoiding the risk of accumulation. Continuousassessment is necessary. cancer pain, methadone, patient-controlled analgesia     

Prolonged disturbance of consciousness and respiratory depression induced by controlled-release morphine, requiring long-term naloxone administration in a hemodialysis patient with cancer--a case report

An 82-year-old female on hemodialysis was diagnosed with advanced breast cancer. She received 20 mg of controlled-release oral morphine per day for the relief of cancer pain. After a total dose of 30 mg was administered, she was hospitalized with disturbance of consciousness. The patient underwent hemodialysis the next day, but developed impaired consciousness and respiratory depression. On the third day of hospitalization, a continuous infusion of naloxone was started and administered for eleven days. Thereafter, she was given oxycodone during hemodialysis without any side effects. Morphine-6-glucuronide(M-6-G)can accumulate in the blood of renal failure and dialysis patients. Toxicity of M-6-G may persist even after this metabolite is removed by dialysis, causing potentially life-threatening opioid toxicity. Morphine is therefore not recommended for use in renal failure and dialysis patients. The use of fentanyl or oxycodone is recommended as an alternative opioid. It is essential that medical staff are aware that these patients have an increased risk of developing serious morphine-related toxicity.     

Comparison of sustained-release morphine with sustained-release oxycodone in advanced cancer patients

The antinociceptive effect of morphine and oxycodone is mediated preferentially at micro and kappa receptors, respectively. The aim of this study was to evaluate the analgesic profile of the combination of morphine and oxycodone in cancer pain, compared to the standard administration of morphine alone. Controlled-release formulations of oxycodone (CRO) and morphine (CRM) were compared in 26 patients. The study started with an open-label, randomised titration phase to achieve stable pain control for 7 days, followed by a double-blind, randomised crossover phase in two periods, 14 days each. At any point, patients were allowed to use oral immediate-release morphine (IRM) as needed, in order to keep visual analogue scale < or =4. Pain, satisfaction, adverse effects and number of daily rescue morphine tablets were assessed. A total of 22 patients were evaluated. The weekly upload consumption ratio in morphine/oxycodone was 1 : 1.8 (1.80, 1.83, 1.76, 1.84). The weekly IRM consumption was higher in patients having CRM compared to patients having CRO (ratio morphine/oxycodone: 1.6, 1.6, 1.6, 1.7) (P<0.05). Patients receiving oxycodone complained of less nausea and vomiting. The rescue morphine analgesic consumption was 38% higher in patients receiving only morphine, compared to patients receiving both morphine and oxycodone. The results suggest that the combination of morphine/oxycodone (opioids with differential preferential sites of action) can be a useful alternative to morphine alone, resulting in a better analgesia profile and less emesis.     

羟考酮缓释片联合即释吗啡在癌痛滴定治疗中的镇痛效果及不良反应

目的:观察盐酸羟考酮缓释片（奥施康定）联合即释吗啡在中、重度癌痛滴定治疗中的镇痛效果及不良反应。方法:选择82例中重度癌痛患者,随机分为A组（即释吗啡）和B组（羟考酮缓释片联合即释吗啡）,通过使用阿片类药物镇痛,对镇痛疗效、起效时间、滴定达到稳态时间、生活质量及不良反应进行观察及评估。结果:两组镇痛效果均显著,比较无明显差异性（P＞0.05）。B组较A组镇痛起效时间明显缩短,比较有明显差异性(P＜0.05),B组较A组滴定达到稳态时间明显缩短,比较有明显差异性(P＜0.05);两组生活质量均明显提高,比较无差异性(P＞0.05);两组便秘及恶心呕吐等不良反应的发生率均低,比较无差异性(P＞0.05）。结论:羟考酮缓释片联合即释吗啡治疗中、重度癌痛起效快、镇痛效果好,不良反应轻。     

羟考酮缓释片联合吗啡片在中重度癌痛滴定治疗中的应用

目的比较羟考酮缓释片联合吗啡片方案和常规吗啡片方案在中重度癌痛滴定治疗中的作用。方法选取2011年1月至2013年5月期间进行滴定治疗的中重度晚期癌痛患者,根据患者入院顺序单双号,将患者分为对照组(100例,采用常规口服吗啡即释片的方式完成滴定治疗)和观察组(100例,采用羟考酮缓释片联合吗啡片方案完成滴定治疗),评价两组患者滴定治疗前后疼痛数字评价量表(NRS)评分、滴定剂量(镇痛维持剂量)、滴定周期数和不良反应发生率。结果对照组患者NRS评分从(7.8±2.4)分降至(1.8±1.3)分,观察组患者从(7.6±2.7)分降至(1.9±1.1)分,两组患者滴定前后NRS评分差异均无统计学意义(P>0.05)。对照组患者滴定剂量为(60.6±29.7)mg/24h,观察组患者为(65.4±32.5)mg/24h,差异无统计学意义(t=0.524,P>0.05)。对照组患者滴定周期为(4.1±2.7)个,观察组患者为(3.2±1.8)个,差异有统计学意义(t=2.360,P<0.05)。两组患者不良反应发生率比较,差异无统计学意义(P>0.05)。结论羟考酮缓释片联合吗啡片滴定方案具有时效优势。     

Strategies to manage the adverse effects of oral morphine: an evidence-based report.

Successful pain management with opioids requires that adequate analgesia be achieved without excessive adverse effects. By these criteria, a substantial minority of patients treated with oral morphine (10% to 30%) do not have a successful outcome because of (1) excessive adverse effects, (2) inadequate analgesia, or (3) a combination of both excessive adverse effects along with inadequate analgesia. The management of excessive adverse effects remains a major clinical challenge. Multiple approaches have been described to address this problem. The clinical challenge of selecting the best option is enhanced by the lack of definitive, evidence-based comparative data. Indeed, this aspect of opioid therapeutics has become a focus of substantial controversy. This study presents evidence-based recommendations for clinical-practice formulated by an Expert Working Group of the European Association of Palliative Care (EAPC) Research NETWORK: These recommendations highlight the need for careful evaluation to distinguish between morphine adverse effects from comorbidity, dehydration, or drug interactions, and initial consideration of dose reduction (possibly by the addition of a co analgesic). If side effects persist, the clinician should consider options of symptomatic management of the adverse effect, opioid rotation, or switching route of systemic administration. The approaches are described and guidelines are provided to aid in selecting between therapeutic options.     

Parenteral opioids in end-of-life care in cancer patients

The ethical obligation to relieve pain and other distressing symptoms in patients with cancer is now receiving increasing attention and concern in palliative and end-of-life care. The vast majority of patients with cancer pain are prescribed opioids in oral formulation. However, a patient at the end of his or her life often needs parenteral administration of opioids as the medical condition deteriorates, irrespective of using sedatives. Controlled release opioid preparations currently available in Japan are CR morphine sulphate, CR oxycodone and transdermal fentanyl patch. The opioids available in injectable preparations are morphine HCL and fentanyl citrate. Accordingly, not only the guideline for switching opioids, so-called "opioid rotation," but the guideline for changing the opioid administration route is also necessary in end-of-life care. The authors specifically indicate when and how to convert opioid administration from the oral to the parental route.     

盐酸羟考酮缓释片联合即释吗啡片用于中重度癌痛患者滴定的疗效

目的:探讨盐酸羟考酮缓释片联合即释吗啡片用于中重度癌痛患者滴定的有效性和安全性。方法:采用数字分级法对疼痛进行评分,对中重度癌痛患者分别使用盐酸羟考酮缓释片10mg和20mg,q12h进行滴定,即释吗啡片10mg处理爆发痛,根据患者疼痛情况调整24h和48h盐酸羟考酮缓释片剂量,记录疼痛的缓解程度和不良反应。结果:85例患者中,通过盐酸羟考酮缓释片联合即释吗啡片滴定后,1h、24h、48h疼痛明显缓解率分别为62.4%、88.2%和100%,不良反应以消化道症状为主,表现为轻中度恶心（22.4%）、呕吐（15.3%）和便秘（38.8%）,均可控制,无尿潴留以及呼吸抑制发生。结论:盐酸羟考酮缓释片联合即释吗啡片对中重度癌痛患者的滴定方式快速、有效、安全及便利。     

羟考酮替换盐酸吗啡减轻阿片类药物耐药的临床研究

目的研究羟考酮替换盐酸吗啡减轻癌症病人对阿片类药物耐药的影响。方法采用前瞻性自身对照试验,以1.5∶1作为各组病人吗啡向羟考酮转换的基础比率,用数字分级评分（NRS）、卡氏行为状态量表评分（KPS）和生活质量评分（QOL）作为转换前后镇痛效果、活动能力及生活质量的评价指标。结果不同剂量组盐酸吗啡与羟考酮的平均转换比率随着吗啡剂量的增加而增加,转换比值与吗啡的的剂量呈一次线性拟合趋势（F=0.003、P=0.954）,大剂量吗啡组比小剂量吗啡组替换后羟考酮的需要量更小。结论应用羟考酮替换大剂量盐酸吗啡止痛是一种减轻阿片类药物耐药的新途径。     

The Opioid Rotation Ratio of Hydrocodone to Strong Opioids in Cancer Patients

Purpose.

Cancer pain management guidelines recommend initial treatment with intermediate-strength analgesics such as hydrocodone and subsequent escalation to stronger opioids such as morphine. There are no published studies on the process of opioid rotation (OR) from hydrocodone to strong opioids in cancer patients. Our aim was to determine the opioid rotation ratio (ORR) of hydrocodone to morphine equivalent daily dose (MEDD) in cancer outpatients.

Patients and Methods.

We reviewed the records of consecutive patient visits at our supportive care center in 2011–2012 for OR from hydrocodone to stronger opioids. Data regarding demographics, Edmonton Symptom Assessment Scale (ESAS), and MEDD were collected from patients who returned for follow-up within 6 weeks. Linear regression analysis was used to estimate the ORR between hydrocodone and MEDD. Successful OR was defined as 2-point or 30% reduction in the pain score and continuation of the new opioid at follow-up.

Results.

Overall, 170 patients underwent OR from hydrocodone to stronger opioid. The median age was 59 years, and 81% had advanced cancer. The median time between OR and follow-up was 21 days. We found 53% had a successful OR with significant improvement in the ESAS pain and symptom distress scores. In 100 patients with complete OR and no worsening of pain at follow-up, the median ORR from hydrocodone to MEDD was 1.5 (quintiles 1–3: 0.9–2). The ORR was associated with hydrocodone dose (r = −.52; p < .0001) and was lower in patients receiving ≥40 mg of hydrocodone per day (p < .0001). The median ORR of hydrocodone to morphine was 1.5 (n = 44) and hydrocodone to oxycodone was 0.9 (n = 24).

Conclusion.

The median ORR from hydrocodone to MEDD was 1.5 and varied according to hydrocodone dose.     

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.     

晚期肺癌癌痛患者口服吗啡转换为芬太尼贴剂的临床疗效

目的探讨晚期肺癌癌痛患者由口服吗啡转换应用芬太尼透皮贴剂的临床疗效。方法59例口服吗啡镇痛不满意的晚期肺癌伴重度癌痛患者,换用芬太尼透皮贴剂止痛,剂量换算公式为：芬太尼透皮贴剂72h剂量（μg/h）=口服吗啡（mg/d）×0．5,根据疼痛评分调整剂量,将疼痛控制在3分以下。数字评分法记录疼痛强度、生活质量和不良反应评分。结果59例晚期肺癌癌痛患者药物转换后疼痛强度明显降低,转换前疼痛评分均值为（6．27±1．15）分,转换后6d为（2．15±0．87）分,15d为（2．03±0．68）分,30d为（1．95±0．73）分（P〈0．01）。总的疼痛缓解率81．35％。转换后生活质量评分明显提高（P〈0．05）,不良反应如恶心／呕吐和便秘发生率降低,但皮肤瘙痒的发生率提高（P〈0．05）。结论无法应用口服吗啡镇痛的晚期肺癌癌痛患者,转换应用芬太尼贴剂后,镇痛效果提高,生活质量得到明显改善。     

盐酸羟考酮缓释片12 小时滴定方案用于中重度癌痛患者的有效性和安全性—前瞻性 随机 开放 多中心 平行对照研究

  目的  阿片类药物是中、重度癌痛治疗的首选药物。目前以缓释阿片类药物为背景的滴定方法的剂量调整时机和方式还需进一步探索。本研究旨在评估盐酸羟考酮缓释片12 h滴定方案用于中重度癌痛患者的有效性和安全性。  方法  选择 2018年2月至2019年12月浙江省24家医院收治的中重度阿片类药物未耐受癌痛患者114例[数字分级法（numerical rating scale,NRS）≥4 分]作为研究对象。筛选出合并1次以上爆发痛且存在中重度以上疼痛（NRS≥4 分）患者87例,按盐酸羟考酮缓释片调整的时间不同分为试验组（12 h滴定组,n=45）和对照组（24 h滴定组,n=42）。试验组起始给予盐酸羟考酮缓释片10 mg并根据疼痛情况给予即释吗啡补救镇痛,12 h后根据即释吗啡量调整剂量,剂量调整为背景剂量+12 h内即释吗啡剂量。对照组起始剂量给予盐酸羟考酮缓释片10 mg q12h,并根据疼痛情况给予即释吗啡补救镇痛,24 h后剂量调整为背景剂量+24 h内即释吗啡剂量/2。比较两组24 、48、72 h的疼痛缓解率、不良反应发生率、即释吗啡补救镇痛情况及使用量、生活质量评分,以及镇痛满意度。  结果  给药后24 、48 、72 h,试验组和对照组均显示出较高的疼痛缓解率,组间比较差异无统计学意义（P>0.05）。相对于对照组,试验组在24 、48 及72 h补救镇痛次数及剂量均显著减少（P<0.05）。两组患者不良反应大多数为轻中度,发生率比较差异无统计学意义（P>0.05）。镇痛满意度水平均较高,组间比较差异无统计学意义（P>0.05）。  结论  在中重度癌痛患者应用盐酸羟考酮缓释片为背景的滴定方案中,12 h调整剂量能有效减少补救镇痛次数及剂量,维持较高的镇痛缓解率和镇痛满意度,安全性良好。      

A randomised controlled study on the use of anti-inflammatory drugs in patients with cancer pain on morphine therapy: effects on dose-escalation and a pharmacoeconomic analysis

The role of non-steroidal anti-inflammatory drugs (NSAIDs) in cancer pain has been well established in the treatment of mild pain and in association with opioids in the treatment of moderate to severe pain. The aim of this study was to verify the effects of NSAIDs on morphine escalation in advanced cancer patients with pain followed-up at home and to assess the pharmacoeconomic implications. A prospective randomised controlled study was carried out in 156 consecutive advanced cancer patients with pain followed-up at home in the period December 1999-December 2000. In this group of patients, 47 were selected with pain progression after 1 week of opioid stabilisation. Patients were randomly assigned to one of two groups: group 'O' patients were treated with continuing opioid escalation according to their clinical needs; group 'OK' received ketorolac 60 mg/daily orally (p.o.) in three doses and then continued opioid escalation according to their clinical situation. Performance status, doses of morphine before and after starting treatment, mean weekly pain intensity (assessed by means of a numerical scale from 0 to 10), mean weekly symptoms intensity, adverse effects and pain mechanisms were recorded. Moreover, drug costs per day in both groups were calculated. Patients who received ketorolac in addition to morphine showed a better analgesia after a week in comparison to the group treated with morphine only (P=0.005). Thereafter, morphine escalation was slower and the maximum morphine dose was lower in the group treated with ketorolac. The incidence and the severity of gastric discomfort was more evident in patients treated with ketorolac, while constipation was significantly increased in patients who received morphine only. Drug costs per day were similar in both groups; statistical differences were observed in patients who started on lower morphine doses (<100 mg/daily) in the two groups (4.3 in the ketorolac-morphine group versus 3.4 in the morphine group; P=0.012). The use of NSAIDs reduces the need for an opioid dose escalation or allows the use of lower doses. Their use is associated with a more intense gastric discomfort, but results in less opioid-related constipation. The eventual additive cost for NSAIDs therapy is negligible, especially in patients taking high doses of morphine.