World Health Organization Ladder Research Articles

An international, open-label, randomised trial comparing a two-step approach versus the standard three-step approach of the WHO analgesic ladder in patients with cancer

Worldwide, cancer pain management follows the World Health Organization (WHO) three-step analgesic ladder. Using weak opioids (e.g. codeine) at step 2 is debatable with low-dose strong opioids being potentially better, particularly in low- and middle-income countries where weak opioids are expensive. We wanted to assess the efficiency, safety and cost of omitting step 2 of the WHO ladder. We carried out an international, open-label, randomised (1 : 1) parallel group trial. Eligible patients had cancer, pain ≥4/10 on a 0-10 numerical rating scale, required at least step 1 (paracetamol) of the WHO ladder and were randomised to the control arm (weak opioid, step 2 of the WHO ladder) or the experimental arm (strong opioid, step 3). Primary outcome was time to stable pain control (3 consecutive days with pain ≤3). Secondary outcomes included distress, opioid-related side-effects and costs. The primary outcome analysis was by intention to treat and the follow-up was for 20 days. One hundred and fifty-three patients were randomised (76 control, 77 experimental). There was no statistically significant difference in time to stable pain control between the arms, P= 0.667 (log-rank test). The adjusted hazard ratio for the control arm was 1.03 (95% confidence interval 0.72-1.49). In the control arm, 38 patients (53%) needed to change to a strong opioid due to ineffective analgesia. The median time to change was day 6 (interquartile range 4-11). Compared to the control arm, patients in the experimental arm had less nausea (P= 0.009) and costs were less. This trial provides some evidence that the two-step approach is an alternative option for cancer pain management.

Cancer pain management at a tertiary care cancer center in India—A retrospective analysis of 3,238 patients

Effective pain control is essential for the management of patients with cancer. About 70-80 percent of patients with cancer present in an advanced stage of disease. Patients with advanced cancer frequently experience intractable pain, with diverse symptoms that can make daily living impossible and affect the quality of life. This article reports the management of 3,238 patients with cancer pain over a period of five years. Nearly 89.6 percent patients had good pain relief with Visual Analogue Scale score less than 3. These promising results were achieved by careful patient assessment, close liaison with clinicians from other specialties, and using a variety of analgesic regimen including oral analgesics, anesthetic procedures, psychological interventions, and supportive care. However, the main stay of treatment was oral analgesics, following the principles of World Health Organization ladder, with continuing follow-up.

Methadone for Pain Management: Past, Present and Future.

Methadone for pain management in this article describes briefly pain, methadone as a Level 3 World Health Organization ladder opioid in the context of India and rest of the world, as well as the relationship to past, present, and future possibilities of pain management. Acute pain is proportional to the injury most of the times, and such proportionality may not exist in chronic pain. Pain management over decades has changed because of knowledge and availability of molecules and compounds to reduce chronic pain. Naturally occurring opioids from “poppy” such as morphine and heroin were available through cultivation and trade for pain management and recreational use in different parts of the world for centuries. Methadone has been a synthetic molecule discovered in the 1930s in Germany. It has been used for harm reduction for opioid use disorder in the form of “methadone maintenance treatment”. This program exists since the 1950s while pain management started around the late 1970s in Europe and North America. More recently, the knowledge of acute and chronic pain at a molecular level, including ion channel modification, allowed the use of coanalgesics and opioids prudently. The concept of “total pain, neuroplasticity, and neurotransmitters” how they could be modified for better pain management with pharmaceuticals and nonpharmacological methods are being investigated, and evidence is being practiced clinically. In the present context, education for physicians, allied health professionals, patients, and family caregivers is important. Education to the physicians can skill and capacity build in the community and can be associated with educational research and peer-reviewed publications. The future remains promising, as innovations such as pharmacogenomics, nanotechnology, molecular, and quantum biology may create evidence, along with physical and psychological rehabilitation, to prevent and holistically better pain management.

Efficacy and Safety of Radium-223 Dichloride in Symptomatic Castration-resistant Prostate Cancer Patients With or Without Baseline Opioid Use From the Phase 3 ALSYMPCA Trial

BackgroundThe phase 3 ALSYMPCA trial enrolled metastatic castration-resistant prostate cancer patients with or without baseline opioid use. ObjectiveTo assess the efficacy and safety of radium-223 dichloride (radium-223) versus placebo in ALSYMPCA patients by baseline opioid use. Design, setting, and participantsNine hundred and twenty one patients enrolled at 136 centers globally. InterventionRadium-223 (50 kBq/kg, intravenous injection) every 4 wk for six cycles or matching placebo, each plus best standard of care. Outcome measurements and statistical analysisPrimary endpoint (overall survival [OS]), main secondary efficacy endpoints, and safety were evaluated by baseline opioid use. Additional analyses included time to first opioid use, time to first external beam radiation therapy for bone pain, and safety of concomitant external beam radiation therapy. Results and limitationsAt baseline, 408 (44%) patients had no pain and no analgesic use or mild pain with nonopioid therapy (World Health Organization ladder pain score 0–1 [nonopioid subgroup]), and 513 (56%) had moderate pain with occasional opioids or severe pain with regular daily opioids (World Health Organization ladder pain score 2–3 [opioid subgroup]). Radium-223 significantly prolonged OS versus placebo in nonopioid (hazard ratio [HR]=0.70; 95% confidence interval [CI]: 0.52–0.93; p=0.013) and opioid (HR=0.68; 95% CI: 0.54–0.86; p=0.001) subgroups, and significantly reduced risk of symptomatic skeletal events versus placebo, regardless of baseline opioid use (nonopioid subgroup: HR=0.56, 95% CI: 0.39–0.82, p=0.002; opioid subgroup: HR=0.72, 95% CI: 0.53–0.98, p=0.038). Time to first opioid use for bone pain was significantly delayed with radium-223 versus placebo (HR=0.62, 95% CI: 0.46–0.85, p=0.002). Adverse event incidences were similar between opioid subgroups. ConclusionsRadium-223 versus placebo significantly prolonged OS and reduced symptomatic skeletal event risk with a favorable safety profile in castration-resistant prostate cancer patients with symptomatic bone metastases, regardless of baseline opioid use. Patient summaryIn this ALSYMPCA opioid subgroup analysis, baseline symptom levels did not appear to impact radium-223 dichloride efficacy or safety.

Pain in pancreatic cancer: review of medical and surgical remedies.

Pancreatic cancer is a malignant tumour with very poor prognosis and a chance for 5-year survival is approximately 6%. One of the main symptoms of this neoplasm is pain, mostly of neuropathic origin, which significantly decreases the quality of life and impairs the functional activity of patients. The most common treatment of pain in pancreatic cancer is conservative therapy which is based on analgesic ladder rules established by the World Health Organization. Unfortunately, it is not always effective and it has many side effects that also can diminish patients' quality of life. Invasive treatment of pain in pancreatic cancer includes mainly coeliac plexus block and sympathectomy, and both of them significantly reduce levels of pain and help to improve the quality of life. It is postulated that the place of those two invasive methods should not be at the final stage of treatment, but they can provide significantly better improvement of pain once instituted earlier (such as the first or second step of analgesic World Health Organization's ladder). The aim of this article is to review and assess the conservative as well as the invasive therapy in the management of pain in pancreatic cancer. It also presents brief insight into non-medical methods of pain reduction, which can be supplementary to conservative and/or invasive treatment.

Neurolytic Sympathectomy in the Management of Cancer Pain—Time Effect: A Prospective, Randomized Multicenter Study

ContextSympathectomy is currently used as the fourth step of the modified World Health Organization (WHO) analgesic ladder. Sympathectomy can be performed early, before the second step on the ladder. ObjectivesWe hypothesized that early sympathectomy would reduce pain and opioid consumption and improve quality of life. MethodsOne hundred nine patients, with inoperable abdominal or pelvic cancer, reporting visceral pain of 40–70 on a visual analogue scale and taking nonopioid analgesics were allocated randomly into two groups: either blocks were performed before Step 2 of the WHO ladder, then analgesics were managed according to the ladder (Group I) or analgesics were given according to the WHO ladder, and blocks were performed as the fourth step after failure of strong opioids to control pain (Group II). Visual analogue scale scores, responder analysis, daily opioid consumption, related side effects, and quality of life were assessed. ResultsResponders were significantly higher in Group I (P < 0.0001), and partial responders and nonresponders significantly increased in Group II (P < 0.0001 and 0.006, respectively). Opioid consumption significantly decreased in Group I (P < 0.0001 during first 12 months and 0.007 at the last assessment time), with concomitant significant reduction in related side effects. The number of patients who had a good analgesic response on tramadol significantly increased in Group I during the first five months (P < 0.05). European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 global quality-of-life subscale scores revealed significant improvement until the fifth month in Group I (P < 0.05). ConclusionSympathectomy before Step 2 on the WHO analgesic ladder seems to lead to better pain control, less opioid consumption, and better quality of life in cancer patients.

Role of percutaneous cervical cordotomy in cancer pain management

Pain control in cancer patients reduces suffering and improves the quality of life. The classic World Health Organization (WHO) analgesic ladder may be effective in controlling cancer pain in 80–90% of patients. In the UK, current application of the principles embodied in the WHO ladder follows a modified algorithm by which interventional techniques should be considered as adjuvant therapy alongside all steps of the analgesic ladder. Recent UK experience suggests that, despite optimization of systemic analgesia, 11% patients in a hospice setting were considered for interventional therapy. The scope of advanced pain management techniques in adult palliative care is contained within the Specialised Services National Definition Set and the full range of interventions has been reviewed elsewhere. This article describes the technique and application of percutaneous cervical cordotomy (PCC) in the management of intractable unilateral cancer pain. Experience of the neurological deficit resulting from tuberculous lesions of the spinal cord caused Spiller to conclude that pain could be relieved by cutting the pain pathway in the spinal cord, leading to the first open surgical cordotomy in 1905. Reports of open cordotomy via thoracic and cervical laminectomy continued until percutaneous techniques were described in the 1960s, initially using a radioactive needle and subsequently with radiofrequency (RF) thermocoagulation. A computed tomography (CT)guided technique has been described, but the vast majority of cordotomies performed in the UK are by percutaneous RF under fluoroscopic guidance.

Ganglion Impar Phenol Injection in a Pediatric Patient with Refractory Cancer Pain

Dear Editor, Cancer pain is still a major issue despite the World Health Organization ladder. Up to 30% of the patients experience poor pain control, especially at late stages and during the last year of life [1]. While opioids are the gold standard for treatment of moderate to severe cancer pain, at least 10–15% may benefit from interventional procedures [2,3]. The main reason to advocate interventional pain management (IPM) is either a lack of efficacy of the opioids and the co-adjuvant therapy or intolerable side effects of such therapy. IPM includes neurolytic procedures (celiac plexus neurolysis, superior hypogastric neurolysis, and impar ganglion neurolysis), continuous epidural and intrathecal analgesia radiofrequency, and vertebral or bone cement augmentation [4]. Most of the IPM experience has been done on adult population, and the information in pediatric population is limited. Neurolytic injection on the impar ganglion is reported since 1990. This ganglion is a single retroperitoneal structure, marking the end of the paired paravertebral sympathetic chains. It is responsible for visceral-perineal pain that is sympathetically maintained [5]. There are no reports of neurolytic impar ganglion injection in …

Palliative Care Knowledge and Attitudes Among Oncology Nurses in Qatar

Formal palliative care (PC) education is lacking in the middle eastern state of Qatar. This study was done to assess the need for PC education among oncology nurses in Qatar. In March 2012, a self-constructed questionnaire was distributed to 115 nurses at the Qatar National Center for Cancer Care and Research. A total of 115 nurses responded to the questionnaire. The majority (87.8%) were female. Although 60% had more than 10 years of work experience, only 31% had received formal training in PC, with only 6.1% having completed postgraduate training. The majority (63%) of responders attributed this issue to unavailability of PC courses rather than lack of time, interest, or financial issues. Currently, only 16.7% did not express interest in the field, with 56% showing some kind of interest. In terms of knowledge, 54% of the responders were familiar with the World Health Organization ladder for pain relief. Only 43.6% know about Palliative Performance Scale, and half of the nurses know the Edmonton Symptom Assessment System. Overall, 56% of the nurses indicated a need for training in more than 1 aspect. These aspects included training in care of the dying patients (14.6%), communication strategies (22%), caregiver support (10.6%), psychosocial care (15%), pain management (10.2%), other symptom management (13%), and other ethical/spiritual issues (14.2%). There is a clear deficiency in formal PC education among the nurses at the National Center for Cancer Care and Research, in Qatar. This is reflected by their lack of experience and exposure to PC and their mediocre knowledge in the field. This could be attributed to the fact that formal PC service was established only recently in Qatar (2008). Formal training courses in PC nursing are required.

Management of cancer pain: ESMO Clinical Practice Guidelines

Management of cancer pain: ESMO Clinical Practice Guidelines

Emerging drugs for cancer-related pain

Most cancer pain can be managed effectively using analgesics according to World Health Organization (WHO) guidelines. This involves a stepwise approach to the use of analgesic drugs. While the validity of the WHO approach has been questioned, the 3-step ladder has been an invaluable tool and has been extensively validated [25, 37, 41]. This standardized approach is a framework of principles and allows flexibility in the choice of analgesics. A substantial minority of patients treated using the WHO ladder do not have a successful outcome because of excessive adverse effects, inadequate analgesia, or a combination of both adverse effects and inadequate analgesia [5]. Drug development in the area of cancer pain has been difficult owing to several reasons. Clinical research is a very difficult issue due to the characteristics of patients who are often unable to participate in long-term studies, because they are unstable. Recently animal models have been developed to mimic cancer pain. They have produced relevant information on the physiopathology, but limited data are available in clinical practice. However, there are new therapeutic strategies and a variety of novel drugs, including opioids and non-opioid drugs, that are based on established concepts with the goal to improve analgesia in patients with cancer-related pain.

Oxycodone and a Useful Book

Opioids are the backbone of the management of moderate to severe pain as defined by the World Health Organization ladder. In most patients, morphine is the favored drug, however, in some the intolerable side effects and lack of efficacy dictates the use of another opioid, such as oxycodone. Oxycodone is a semisynthetic derivative of thebaine, an opium alkaloid, and can also be made by modifying morphine. It has the same structural relationship to codeine that oxymorphone has to morphine and is a potent opioid mu-receptor agonist. Oxycodone is 10 times as potent as codeine and is demethylated and conjugated in the liver. It is excreted in the urine with part of its analgesic effect mediated by active metabolites. The half-life is 2 to 3 hours and the duration of action is 4 to 5 hours. Oxycodone is at least half as potent orally as administered parenterally, so it is usually given orally. In a study of 20 patients, Glare and Walsh found single-entity oxycodone to be equianalgesic with morphine when using the oral route during chronic administration for cancer pain. Oxycodone has been used clinically since 1917, with varying patterns of use worldwide. The annual use of oxycodone has increased 42-fold in the United Kingdom and 3-fold in the United States from 1999 to 2003. It is widely used in the United States in a low dose combined with a nonopioid analgesic drug. The formulation is usually given as a tablet containing 5 mg oxycodone in a fixed combination with a nonopioid analgesic such as acetaminophen (Percocet, Endocet, Tylox) or aspirin (Percodan, Endodan) to name a few examples. It is considered a weak opioid analgesic because the dose cannot be increased above 10 mg every 4 hours due to the risk of liver damage from acetaminophen or gastrointestinal distress from aspirin. However, based on their study, Glare and Walsh have advocated that single-entity oxycodone be reclassified as a strong opioid analgesic. In a follow up to the initial study, Glare and Walsh studied 24 patients with advanced cancer and chronic pain who were treated with oxycodone every 4 hours. Of the 24 patients, 20 completed the study. The median starting dose was 15 mg (range of 5 to 30 mg) and of the 20 patients who completed the study, the median stable dose was 20 mg (range of 15 to 60 mg). Although not statistically significant, patients less than 65 years had a higher median stable dose, that is, 45 mg versus 20 mg for the older patients. Side effects were mild, commonly being sedation, constipation, and nausea/vomiting. Pain relief was achieved with doses up to 60 mg every 4 hours and was the preferred analgesic in the vast majority of the patients. Several interesting observations were made by the authors from this study. First, the effective doses of oxycodone were similar to oral morphine with most patients experiencing pain relief at a dose of 30 mg every 4 hours or less. Second, patients older than 65 years required less oxycodone, which is like the pharmacokinetics of morphine where patients older than 50 years have significantly higher plasma levels than those younger than 50 years given the same single doses. Third, the side effects of oxycodone did not differ from other opioids. Finally, the authors concluded that oral oxycodone was versatile, flexible, and provided durable analgesia in patients with advanced cancer and chronic pain much like oral morphine. In a more recent study, Reid et al reported the results of a meta-analysis of randomized controlled trials on the use of oxycodone for cancer-related pain. Four studies comparing oral oxycodone to either oral morphine or oral hydromorphone were ultimately identified and analyzed. The study found no differences between analgesic efficacy or the adverse side effect profile of oxycodone compared to morphine, again, confirming the use of oxycodone for cancer-related pain. In this issue of the Journal, Mercadante et al report the results of their study of the use of high dose oxycodone in an acute palliative care unit. The reader is encouraged to read the entire article, but this study confirms the previous findings that oxycodone, including the controlled release formulation, is safe and as effective as morphine in the treatment of chronic pain and that doses were significantly lower in older patients. So, after the above review of the use of oxycodone rather than morphine for the treatment of chronic pain, what is the equianalgesic ratio of the 2 drugs? Cannot remember? Do not know where to look? Well, a good source for this answer is the just published book entitled Demystifying Opioid Conversion Calculations. A Guide for Effective Dosing by Mary Lynn McPherson. Dr McPherson is Professor and Vice Chair,

Opioid Rotation in the Management of Chronic Pain: Where Is the Evidence?

The management of chronic pain remains a challenge because of its complexity and unpredictable response to pharmacological treatment. In addition, accurate pain management may be hindered by the prejudice of physicians and patients that strong opioids, classified as step 3 medications in the World Health Organization ladder for cancer pain management, are reserved for the end stage of life. Recent information indicates the potential value of strong opioids in the treatment of chronic nonmalignant pain. There are, up until now, insufficient data to provide indications about which opioid to use to initiate treatment or the dose to be used for any specific pain syndrome. The strong inter-patient variability in opioid receptor response and in the pharmacokinetic and pharmacodynamic behavior of strong opioids justifies an individual selection of the appropriate opioid and stepwise dose titration. Clinical experience shows that switching from one opioid to another may optimize pain control while maintaining an acceptable side effect profile or even improving the side effects. This treatment strategy, described as opioid rotation or switch, requires a dose calculation for the newly started opioid. Currently, conversion tables and equianalgesic doses are available. However, those recommendations are often based on data derived from studies designed to evaluate acute pain relief, and sometimes on single dose studies, which reduces this information to the level of an indication. In daily practice, the clinician needs to titrate the optimal dose during the opioid rotation from a reduced calculated dose, based on the clinical response of the patient. Further research and studies are needed to optimize the equianalgesic dosing tables.

Radiofrequency and cryoablation for cancer pain

Prevalence of pain in patients with cancer is high and is a feared and burdensome symptom. There has been a paradigm shift away from the World Health Organization ladder with adoption of interventional treatments early on in the treatment of cancer pain. Intentional destruction of nerves (neurolysis) with chemical (alcohol or phenol), heat (radiofrequency), or cold (cryo) are treatment modalities used to treat cancer pain. These management modalities have become both mainstays of cancer pain therapy and adjuvants to medical management. Chemical neurolysis with phenol or alcohol are commonly used for sympathetic neurolysis. Radiofrequency ablation (conventional and pulsed) and cryoablation are widely used in the treatment of nonmalignant pain. The published data on the use of theses modalities in the cancer population consist mainly of case reports. At the University of Texas MD Anderson Cancer Care Center, neuroablative techniques are frequently used to control refractory cancer pain. The evolution, histologic effect of radiofrequency and cryoablation, and their application are reviewed herein. Common clinical applications and specific techniques conducted at MD Anderson Cancer Care Center are used as examples of how these techniques can be applied to treat cancer related pain.

Decision-making in the cancer pain setting: Beyond the WHO ladder

The treatment of cancer-related pain is an area of great concern to patients and physicians alike. In the recent past, emotional reactions, societal pressure, and misinformation guided physicians in their choice of treatment modalities and often led to undertreated pain. The development of the World Health Organization ladder for guiding the treatment of cancer pain helped to not only guide physicians in the proper use of opioids, but also to break down social and legal barriers to their proper use. The World Health Organization ladder has also constrained physicians when used in a purely mechanistic manner. Despite the aggressive use of opioids and adjuvant medications, 10%-20% of patients with cancer pain suffer with severe pain. This underscores the need to move beyond the ladder concept and into a paradigm of multimodal care. The early inclusion of interventional pain management before patients have been maximized on opioids should be considered. Such procedures include percutaneous vertebroplasty, percutaneous kyphoplasty, and neurolytic celiac plexus block. Use of a multimodal pain management regimen should help to decrease suffering and side effects, and improve quality of life for cancer patients.

The Use of Opioid Analgesia in End-Stage Renal Disease Patients Managed Without Dialysis

The numbers of patients dying with end-stage renal disease (ESRD), particularly those managed conservatively (without dialysis) or withdrawing from dialysis is increasing rapidly in developed countries. There is growing awareness of the extensive symptom control needs of these patients. Pain is a common problem, and has been both under-recognized and under-treated. It is challenging to manage, largely because of the constraints very poor renal function places on use of medication. Although pharmacological reviews of opioid use in renal failure have been published, there is a need for clinical recommendations to aid palliative and renal specialists in providing effective pain control. This review describes the pharmacological evidence for and against the use of the different opioid medications, and translates this into clinical recommendations for ESRD patients managed conservatively, not for those on dialysis for whom there are different pharmacological considerations. Acetaminophen (paracetamol) is recommended at Step 1 of the World Health Organization ladder. Of the Step 2 analgesics, tramadol is the least problematic, although dose reduction and increased dosing interval are required, and caution should be exercised. Of the Step 3 analgesics, fentanyl, alfentanil and methadone are recommended. There is limited evidence for buprenorphine, although theoretical reasons why it may be a good choice for these patients. Hydromorphone and oxycodone cannot be recommended because of extremely limited evidence, although each is likely a better choice than morphine or diamorphine. Morphine and diamorphine themselves are not recommended because of known accumulation of potentially toxic metabolites.

Use of the World Health Organization guidelines on cancer pain relief before referral to a specialized pain service

In 1986 the World Health Organization (WHO) released guidelines for cancer pain relief. Since then, several controlled studies on effectiveness and practicability of these guidelines have been published. Various authors described inadequate use of these guidelines. We analysed, whether the pain medication of 160 cancer patients referred to the anesthesiological pain clinic at the university hospital of Vienna corresponded to the WHO guidelines or not. Adequacy of pain treatment was assessed using the pain management index (PMI). Multiple criteria were chosen to assess the conformity of the treatment with the guidelines. Furthermore we studied the effect of a strict use of the WHO guidelines in these patients. The average pain intensity of the referred patients was 75 mm (VAS). Negative PMI scores, indicating inadequate pain therapy, were found in 39 % of cases. A violation of the rules was found in 38% of the therapy schedules. Pain medication was then modified by switching to fixed time intervals, escalation of the steps of the WHO ladder, increasing the dosage or treating neuropathic pain with adjuvant drugs. Two weeks later the average pain score of the patients was reduced to 27 mm (VAS). At that time 72% of the patients quoted an adequate reduction of pain. Inadequate knowledge or disregard of the WHO guidelines for cancer pain relief are common and result in unnecessary and prolonged suffering in these patients.

Cancer pain and neurolysis

C ancer related pain is still a problem that affects many patients despite advances in detection and treatment of cancer. It is estimated that more than 1.2 million new cases of cancer (excluding skin cancer) will be diagnosed in 2002 and approximately one-half of a million people will die in the United States as a result of cancer. ~ It is the second leading cause of death after heart diseases with I of every 4 deaths because of cancer in the US. ~ Unforttmately, a significant portion of patients continue to experience moderate to severe pain during the latter stages of cancer. Advances in cancer treatment continue to increase survival among cancer patients. In fact, as the overall survival of these patients improved, pain as a consequence of the disease and its treatment will become more prevalent. Pain is a common symptom in cancer and next to incurability, it is the most teared complications. Thus, quality of life has increasing importance, The incidence of pain in patients with cancer depends on the type and stage of the disease. It is estimated that 40% of patients experience moderate to severe pain in the intermediate stage while 75-90% of patients have moderate to severe pain with advanced cancer. 2 The World Health Organization (WHO) developed an analgesic ladder to help provide treatment lbr cancer pain more than a decade ago, The WHO ladder is a three tier protocol for the selection of pain medication depending on severity of the pain. It outlines the use of nonopioid, opioid, and adjuvant analgesics, alone or in combination (Fig. I ). When initiating therapy, it is important that the patient start at the appropriate step of the ladder. For mild pain. the patient should start with nonopioid analgesics (step 1); opioids for moderate pain (step 2); more potent opioids for severe pain (step 3). For most cancer patients this ladder has been effective to control pain. However, despite this ladder, 10-30% of patients continue to have inadequately controlled pain or intolerable side effects from these medicat ions) Such side effects include dry mouth, drowsiness, constipation, and nausea and vomiting. In addition, one must recognize that opioids may not be an effective treatment for neuropathic pain. 4'5 Hence, a revised approach to cancer pain treatment that incorporates interventional analgesic techniques has been developed and includes use of neuroablative procedures and neuraxial delivery of analgesic medication (Fig. 2). ~'

Cancer pain: an update of pharmacological approaches in pain therapy

This review discusses clinically oriented data on advances in pharmacological research of cancer pain therapy carried out during the last year. The aim is to ascertain whether well known guidelines for cancer pain prove to be adequate or require modification. There are alternatives to morphine, which is the standard drug, including oxycodone or methadone, with the problem of equivalence doses in the case of opioid rotation. Depending on the underlying pathophysiological mechanisms, adjuvant drugs are recommended, such as antidepressants and anticonvulsants for neuropathic pain, or bisphosphonates for metastasis bone pain. Current and future research will offer receptor-specific acting new drugs or old drugs under new indications. The recommendations of the World Health Organization ladder remain the mainstay of cancer pain management. These recommendations, however, are based more on expert opinions than on evidence-based data.

Tramadol in musculoskeletal pain--a survey.

The three-step analgesic ladder, originally proposed for cancer pain relief by the World Health Organization (WHO), is now widely employed for all types of pain, including the chronic pain of musculoskeletal disease. Tramadol, an analgesic with weak opioid receptor affinity and possessing monoaminergic activity, has proved suitable for use at Step 2 of the WHO ladder. Owing to its pharmacological properties, tramadol is more appropriate than NSAIDs for patients suffering from gastrointestinal and renal problems. Importantly, the analgesic potency of tramadol is greater than that of NSAIDs and of other weak opioids (codeine, dextropropoxyphene). It also causes fewer opioid-type adverse effects, e.g. nausea, drowsiness, vomiting, dry mouth and constipation. In chronic musculoskeletal pain it is recommended that tramadol should be given by mouth and by the clock; the initial dose should be titrated upward gradually to reach the individual level required for suitable pain control. This dosage strategy will also minimise the usual opioid-type adverse effects encountered with tramadol. Four recent publications are reviewed to illustrate the efficacy of tramadol, alone or in conjunction with an NSAID, in the management of low back pain, osteoarthritis pain and breakthrough pain.