Tramadol as an analgesic for mild to moderate cancer pain

In most cancer patients, pain is successfully treated with pharmacological measures such as opioid analgesics alone or opioid analgesics combined with adjuvant analgesics (co-analgesics). Opioids for mild-to-moderate pain (formerly called weak opioids) are usually recommended in the treatment of cancer pain of moderate intensity. There is a debate whether the second step of the WHO analgesic ladder, which, in Poland, is composed of opioids such as tramadol, codeine, dihydrocodeine (DHC), is still needed for cancer pain treatment. One of the most interesting and useful drugs in this group is tramadol. Its unique mechanism of action, analgesic efficacy and profile of adverse effects are responsible for its successful use in patients with different types of acute and chronic pain, including neuropathic pain. The aim of this article is to summarize the data regarding pharmacodynamics, pharmacokinetics, possible drug interactions, adverse effects, dosing guidelines, equipotency with other opioid analgesics and clinical studies comparing efficacy, adverse reactions and safety of tramadol to other opioids in cancer pain treatment.     

Management of pain in the elderly at the end of life

Pain is one of the symptoms most frequently encountered in elderly patients at the end of life. The management of pain in the elderly in general has been associated with undertreatment. The geriatric population has been identified as a challenging population with respect to pain management because of issues related to co-morbidities, polypharmacy and cognitive dysfunction. In the geriatric population, the assessment of pain requires measurement of pain intensity, delineation of opioid responsiveness, and clarification of the impact of pain on patients' psychological, social, spiritual and existential domains. Effective pain management is guided by the World Health Organization (WHO) analgesic stepladder, which categorizes pain intensity according to severity and recommends analgesic agents based on their strength and works effectively in the elderly patient population. Step 1 is reserved for mild pain. Patients in this category are treated with nonopioid analgesics such as acetaminophen, or a nonsteroidal anti-inflammatory, with consideration of an adjuvant analgesic if necessary. Step 2 is reserved for patients experiencing mild to moderate pain who are already taking a nonopioid analgesic, with or without an adjuvant analgesic, but are still experiencing poor analgesic control. Step 2 agents include acetaminophen products containing hydrocodone, oxycodone, codeine and tramadol. Patients with moderate to severe pain require strong analgesics belonging to step 3 of the WHO analgesic stepladder. Step 3 opioids include morphine, hydromorphone, fentanyl, levorphanol, methadone and oxycodone. Familiarity with opioid pharmacokinetics, equianalgesic dosing and adverse effects is necessary for the safe and effective use of these drugs. The appropriate use of adjuvant analgesics such as antiepileptic drugs, antidepressants and local anaesthetics can enhance the use of opioids, especially in cases where opioid responsiveness may be in question, such as with neuropathic pain. This paper will provide an overview of the analgesic considerations for elderly patients at the end of life.     

The importance of non-opioid analgesics for cancer pain relief according to the guidelines of the World Health Organization.

In a retrospective study of 1070 cancer patients being treated according to guidelines of the World Health Organization during a period of 55,285 days, the importance, efficacy and side-effects of non-opioid analgesics were evaluated. The non-opioids were given alone on 6917 days and in combination with weak opioids on 15,253 days, with strong opioids on 24,246 days and with spinal opioids on 1008 days. In evaluating efficacy and safety, it was not possible to differentiate adequately between the effects of non-opioids, opioids and adjuvant drugs, but it was demonstrated that an adequate combination of these drugs was effective and safe in the treatment of cancer pain.     

The clinical usefulness of agonist-antagonistic opioid analgesics in chronic pain

The mixed agonist-antagonist analgesics do not have a major role in the treatment of chronic pain. Pentazocine, the first and most widely used of this group of drugs has two major limitations: by mouth it is not a strong analgesic, but is closer in efficacy to the peripherally acting drugs aspirin and paracetamol than the weak opioids; and its use is associated with psychotomimetic side effects in 10–20 percent of patients. The weak opioid analgesics codeine and dextropropoxyphene are more effective and better tolerated than pentazocine.

Buprenorphine is the most useful of the agonist-antagonists in chronic pain patients. It is potent, long-acting (6–9 h) and effective when given sublingually. However, it has a limited effective dose range and produces the same side effects as morphine-like drugs, possibly more frequently at equianalgesic doses. It may be used in the treatment of cancer pain, or in patients with chronic arthritides or other forms of chronic non-cancer pain who require a potent conventional analgesic, as an alternative to the weak opioids or to morphine in low doses.

Nalbuphine and butorphanol are only available for parenteral administration which means that their usefulness in the treatment of chronic pain is limited. Meptazinol is restricted by its manufacturers to ‘short term’ treatment and there is little information on its use in chronic pain patients.     

Related articles

Pain affects patients with cancer at any stage of their disease. Yet, it is not adequately treated in a significant percentage of cases. In 1986, the WHO proposed a three-step approach for the treatment of pain in cancer patients (from nonopioids to weak opioids to strong opioids, according to pain intensity) following the recommendations of an international group of experts. The application of the WHO strategy demonstrated that a clear and simple approach is of educational value and ensured worldwide dissemination. However, there is little evidence that the WHO approach is the best, and there are still several points to debate on the treatment of cancer pain.     

阿片类药物治疗老年中重度癌痛不良反应分析

目的探讨阿片类药物治疗老年中重度癌痛不良反应。方法采用回顾性分析的方法,分析了100例老年肿瘤患者应用阿片类药物治疗中重度疼痛的不良反应。采用面部表情疼痛分级量表和数字评定量表综合评定疼痛强度。初次使用强阿片类药物的患者从小剂量开始药物滴定,未达到满意止痛效果者,根据剂量换算确定起始剂量。每天定时记录患者疼痛强度、部位、性质和毒副反应等。结果 100例患者用药时间中位值50d,阿片类药物剂量中位值60mg。93%(93/100)以上的患者达到中度以上缓解。患者不良反应发生率为61%(61/100)。便秘为最常见的(48%)不良反应,其次为恶心/呕吐(24%),嗜睡(12%)、头晕(5%)、皮肤瘙痒(5%)、排尿困难(4%),呼吸抑制(2%)的不良反应较少见。结论阿片类药物能够有效控制老年癌痛,主要不良反应为便秘和恶心呕吐。     

Do <Emphasis Type="Italic">CYP2D6</Emphasis> genotypes reflect oxycodone requirements for cancer patients treated for cancer pain? A cross-sectional multicentre study

Objective  

Opioids are recommended by the World Health Organization for moderate to severe cancer pain. Oxycodone is one of the most commonly used opioids and is metabolized in the liver by CYP3A4 and CYP2D6 enzymes. The aim of this cross-sectional study was to assess the relationship between oxycodone pharmacokinetics, pharmacodynamics and the CYP2D6 genotypes “poor metaboliser” (PM), “extensive metaboliser” (EM) and “ultra-rapid metaboliser” (URM) in a cohort of patients with cancer pain.     

The appropriate treatment of chronic pain

Chronic pain is a common healthcare problem worldwide that ranks as a predominant reason for consulting a physician, yet effective management of chronic pain remains suboptimal, often resulting in unnecessary suffering and decreased quality of life, lost productivity and excessive healthcare costs. To overcome the challenges associated with the management of chronic pain, increased awareness and both patient and physician education are required. Improving physician knowledge of pain assessment and management guided by recommendations for a comprehensive, multifactorial, personalised treatment approach involving pharmacological and non-pharmacological approaches is key to achieving effective pain relief. Guidelines for the management of non-cancer and cancer pain recommend thorough patient assessment before individualized therapy based on the type and intensity of pain. The availability of mechanism-specific analgesics has facilitated improvements in the treatment of chronic non-cancer pain, which may be of neuropathic, muscle, inflammatory, mechanical/compressive or mixed origin. Stepwise escalation of analgesic therapy (paracetamol, non-steroidal anti-inflammatory drugs, mild to strong opioids) according to the World Health Organization's three-step pain ladder remains the standard approach for the selection of treatment for chronic cancer pain, although there is now a greater awareness of the requirements for effective administration of opioids including dose titration, use of short versus long-acting opioids, opioid rotation, management of adverse effects, and ongoing monitoring. Selection of an effective, appropriate, personalized analgesic regimen for patients with chronic pain is achievable and is expected to enhance compliance, overall functioning and quality of life.     

Pharmacogenetics of opioids for the treatment of acute maternal pain during pregnancy and lactation

There have been an increasing number of clinical studies investigating the relationship between interindividual genetic variability and the safety and efficacy of opioid analgesics. Despite the widespread use of opioids in pregnant and lactating women for the treatment of acute pain, few studies have investigated the interplay of genetic factors and pregnancy-related physiological alterations in relation to opioid metabolism and response. Some interesting avenues of research require further pursuit- including evidence of cytochrome P450 2D6 (CYP2D6) induction during pregnancy and its effect on the generation of the active opioid metabolites morphine, oxymorphone, O-desmethyltramadol, and hydromorphone following the administration of codeine, oxycodone, tramadol, and hydrocodone respectively. Studies investigating the duration of maternal CYP2D6 induction after delivery are also needed to shed light on genotype to phenotype correlations in breastfeeding mothers using opioid analgesics in the postpartum period.     

Pharmacological treatments for persistent non-malignant pain in older persons

Persistent non-malignant pain is common, often neglected and under-treated among older persons. Some older adults do not complain because they consider chronic pain to be a characteristic of normal aging. Physicians have concerns regarding adverse effects of pharmacological treatment. The model of the World Health Organization for treatment of cancer pain is generally accepted and also recommended for persistent non-cancer pain. Furthermore, non-pharmacological treatment should complement drug treatment whenever possible. An initial assessment and possible treatment of underlying causes of pain are pertinent. Modern pharmacological pain management is based on non-opioid and opioid analgesics. NSAIDs are among the most widely prescribed class of drugs in the world. The new cyclo-oxygenase-2 inhibitors such as celecoxib and rofecoxib offer an alternative for the treatment of mild-to-moderate pain in patients with a history of gastric ulcers or bleeding. Paracetamol (acetaminophen) is being used widely for the management of mild pain across all age groups as it has moderate adverse effects at therapeutic dosages. For moderate pain, a combination of non-opioid analgesics and opioid analgesics with moderate pain relief properties (e.g. oxycodone, codeine, tramadol and tilidine/naloxone) is recommended. For severe pain, a combination of non-opioid analgesics and opioid analgesics with strong pain relief properties (e.g. morphine, codeine) is recommended. The least toxic means of achieving systemic pain relief should be used. For continuous pain, sustained-release analgesic preparations are recommended. Drugs should be given on a fixed time schedule, and possible adverse effects and interactions should be carefully monitored. Adjuvant drugs, such as antidepressants or anticonvulsants, can be very effective especially in the treatment of certain types of pain, such as in diabetic neuropathy. Effective pain management should result in decreased pain, increased function and improvement in mood and sleep.     

The management of chronic pain in important patient subgroups

Chronic pain is a major healthcare issue in Europe and globally, and inadequate or undertreated pain significantly reduces the ability of many patients to participate in ordinary daily activities, adversely affects their employment status and contributes to a substantial rate of depression and anxiety in patients with chronic pain. There is a broad distinction of chronic pain into chronic non-cancer pain and chronic cancer pain, and important subgroups of these include patients with rheumatic and/or orthopaedic diseases, pain syndromes caused by cancer itself and caused by cancer treatment. Despite comprising the majority of non-cancer pain in Europe, chronic non-cancer pain associated with rheumatic diseases and/or orthopaedic conditions is often inadequately managed. Although paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) play a continuing role in the treatment of chronic rheumatic diseases, accumulating evidence of potential toxicity with both traditional non-selective NSAIDs and selective cyclooxygenase 2 inhibitors has prompted a reassessment of their use. This has particular resonance for the elderly, who are more likely to have significant pain issues than younger patients and are at high risk of NSAID-related adverse events. The use of mild opioids, such as codeine and tramadol, and strong opioids, such as morphine, hydromorphone and oxycodone, may be appropriate where paracetamol and other non-opioid analgesics are ineffective in chronic non-cancer pain. Cancer pain, either related to the underlying disease or caused by cancer treatment, is also a common cause of chronic pain in the elderly. An understanding of individual needs is essential in providing adequate pain relief, which is a central goal of care in all patients with chronic pain.     

Tramadol--the impact of its pharmacokinetic and pharmacodynamic properties on the clinical management of pain

Tramadol (CAS 36282-47-0) plays an important role in the management of pain. With its dual mechanism of action (opioid agonist; weak noradrenaline and serotonin reuptake inhibitor) tramadol provides a kind of combined/adjuvant pain therapy. Besides its proven clinical efficacy tramadol is a safe drug as respiratory depression, cardiovascular side effects, drug abuse and dependence are of minor clinical relevance, unlike some other opioids. Following oral administration the bioavailability of tramadol is high (70-90%) and with new slow release preparations twice daily administration enables effective pain control. Tramadol is characterised by low plasma protein binding (20%) and quite extensive tissue distribution (apparent volume of distribution about 3 l/kg). Elimination is primarily by the hepatic route (metabolism by CYP2D6 to an active metabolite and by CYP3A4 and CYP2B6) and partly by the renal route (up to 30% of dose). Elimination half-lives of the active agents range between 4.5 and 9.5 h and total plasma clearance of tramadol is moderately high (600 ml/min). The interaction potential of tramadol is neglectable, as it does not affect the disposition of other drugs. It should be taken into account that inducers (e.g. carbamazepine) or inhibitors (e.g. quinidine for CY2D6) of drug metabolism might modify the elimination of tramadol. Likewise, if kidney (creatinine clearance below 30 ml/min) or hepatic function is severely impaired, some dosage reduction (approximately by 50%) or extension of the dosage interval should be considered. In conclusion, tramadol is an effective and safe analgesic with a very low interaction potential. Therefore it represents a drug of first choice if moderate to severe pain states have to be treated in pediatric, adult and elderly patients including those with poor cardiopulmonary function.     

阿片受体的晶体结构和基因多态性研究进展

阿片受体是阿片类镇痛药的重要作用靶点,中度至重度疼痛的治疗大部分依赖于阿片类药物的使用。目前临床上常用的吗啡等阿片类镇痛药治疗指数窄并且具有较大的个体差异。而且常常伴随着一些严重的耐受性和成瘾性等副作用。深入认识阿片受体高分辨率结构特点,有助于一些基于结构研发的方法中开发治疗疼痛及成瘾药物。研究阿片受体的基因多态性有助于从分子生物学的角度解释个体间对阿片类药物反应存在的差异。     

The management of severe chronic pain with a focus on new treatment modalities

Pain is the most common reason for consultation with a physician, but because pain is not objectively measurable, it is often neglected or underestimated. Chronic, severe pain is a major complication of cancer and HIV-1 infection. Current therapy typically employs stepwise treatment first with nonopioid analgesics, followed by weak and then strong opioids. Nevertheless, treatment can be limited both by side effects and by the development of tolerance, and patients with neuropathic pain are often resistant to all conventional therapies. Much has been learned about the neuroanatomy and physiology of both acute and chronic pain. Drugs now being developed, such as alpha(2)-receptor agonists, the N-type calcium channel blocker, SNX-111 and NMDA antagonists, take advantage of current knowledge of the neurochemistry of pain transduction and target neurotransmitter modulation as a means of achieving analgesia. These new drugs and alternative administration methods, such as intraspinal drug delivery and preemptive analgesia for postoperative pain, should add substantially to the current analgesic armamentarium.     

Perioperative pain management

The under-treatment of postoperative pain has been recognised to delay patient recovery and discharge from hospital. Despite recognition of the importance of effective pain control, up to 70% of patients still complain of moderate to severe pain postoperatively.The mechanistic approach to pain management, based on current understanding of the peripheral and central mechanisms involved in nociceptive transmission, provides newer options for clinicians to manage pain effectively. In this article we review the rationale for a multimodal approach with combinations of analgesics from different classes and different sites of analgesic administration. The pharmacological options of commonly used analgesics, such as opioids, NSAIDs, paracetamol, tramadol and other non-opioid analgesics, and their combinations is discussed. These analgesics have been shown to provide effective pain relief and their combinations demonstrate a reduction in opioid consumption.The basis for using non-opioid analgesic adjuvants is to reduce opioid consumption and consequently alleviate opioid-related adverse effects. We review the evidence on the opioid-sparing effect of ketamine, clonidine, gabapentin and other novel analgesics in perioperative pain management. Most available data support the addition of these adjuvants to routine analgesic techniques to reduce the need for opioids and improve quality of analgesia by their synergistic effect. Local anaesthetic infiltration, epidural and other regional techniques are also used successfully to enhance perioperative analgesia after a variety of surgical procedures. The use of continuous perineural techniques that offer prolonged analgesia with local anaesthetic infusion has been extended to the care of patients beyond hospital discharge.The use of nonpharmacological options such as acupuncture, relaxation, music therapy, hypnosis and transcutaneous nerve stimulation as adjuvants to conventional analgesia should be considered and incorporated to achieve an effective and successful perioperative pain management regimen.     

Pharmacogenetics of analgesics: toward the individualization of prescription

The use of analgesics is based on the empiric administration of a given drug with clinical monitoring for efficacy and toxicity. However, individual responses to drugs are influenced by a combination of pharmacokinetic and pharmacodynamic factors that can sometimes be regulated by genetic factors. Whereas polymorphic drug-metabolizing enzymes and drug transporters may affect the pharmacokinetics of drugs, polymorphic drug targets and disease-related pathways may influence the pharmacodynamic action of drugs. After a usual dose, variations in drug toxicity and inefficacy can be observed depending on the polymorphism, the analgesic considered and the presence or absence of active metabolites. For opioids, the most studied being morphine, mutations in the ABCB1 gene, coding for P-glycoprotein (P-gp), and in the micro-opioid receptor reduce morphine potency. Cytochrome P450 (CYP) 2D6 mutations influence the analgesic effect of codeine and tramadol, and polymorphism of CYP2C9 is potentially linked to an increase in nonsteroidal anti-inflammatory drug-induced adverse events. Furthermore, drug interactions can mimic genetic deficiency and contribute to the variability in response to analgesics. This review summarizes the available data on the pharmacokinetic and pharmacodynamic consequences of known polymorphisms of drug-metabolizing enzymes, drug transporters, drug targets and other nonopioid biological systems on central and peripheral analgesics.     

芬太尼透皮贴剂治疗中重度癌性疼痛的临床观察

目的：观察芬太尼透皮贴剂治疗中重度癌性疼痛的疗效及不良反应。方法：对56例中重度癌痛的患者使用芬太尼透皮贴剂治疗,初治患者最初剂量中度疼痛从25μg.h^-1开始使用,重度疼痛可从25μg.h^-1开始,随着患者的反应逐步提高剂量。曾用过强阿片类药物的患者则根据患者用药情况进行剂量转换[芬太尼透皮贴剂的剂量（μg.h-1,q72.h^-1）=口服吗啡的剂量（mg.d^-1）×1/2]。用药后根据患者疼痛缓解情况剂量调整,按照25μg.h^-1剂量增加,直至疼痛缓解。用药期间严密观察药物剂量的调整、疗效、耐受性、药物依赖性、不良反应等。结果：全组患者完全缓解43例（76.8%）、部分缓解9例（16.1%）,总缓解率92.9%（52/56）。主要的不良反应是便秘,头晕、恶心、呕吐、皮肤瘙痒等,发生率很低。结论：芬太尼透皮贴剂治疗中重度癌性疼痛疗效确切,不良反应轻微,耐受性好,可作为口服强阿片类药物外的替代治疗,尤其适用于不能口服止痛药的患者。     

Weak opiate analgesics: modest practical merits

(1) The first-line drugs for mild to moderate pain are non opiate analgesics, namely paracetamol and nonsteroidal antiinflammatory drugs (NSAIDs). (2) Codeine, dextropropoxyphene and tramadol are weak opiates; they are often used with paracetamol in fixed-dose combinations, in order to reinforce the analgesic effect of paracetamol. (3) These analgesic combinations have only been evaluated in a few situations associated with chronic and acute pain. And the endpoints used in clinical trials are designed more to show statistically significant differences than clear clinical differences. (4) In acute pain, available meta-analyses confirm that the first-line drug is paracetamol, or, if necessary, ibuprofen, a NSAID. (5) The paracetamol + codeine combination slightly increases the analgesic effect of paracetamol, but causes more adverse effects. Combinations of paracetamol + dextropropoxyphene and paracetamol + tramadol are even less useful. (6) The few available clinical trials fail to demonstrate that combining paracetamol with a NSAID is any more effective than either drug given alone, while adverse effects are increased. (7) Paracetamol is also the first-line treatment for chronic non cancer pain, such as low back pain or pain due to osteoarthritis of the hip. NSAIDs have no advantages over paracetamol in these settings. We found no trials of paracetamol + NSAID combinations. Combinations of paracetamol and weak opiates have been inadequately studied in this situation, and are only second-line options.