Influence from genetic variability on opioid use for cancer pain: a European genetic association study of 2294 cancer pain patients.

Cancer pain patients need variable opioid doses. Preclinical and clinical studies suggest that opioid efficacy is related to genetic variability. However, the studies have small samples, findings are not replicated, and several candidate genes have not been studied. Therefore, a study of genetic variability with opioid doses in a large population using a confirmatory validation population was warranted. We recruited 2294 adult European patients using a World Health Organization (WHO) step III opioid and analyzed single nucleotide polymorphisms (SNPs) in genes with a putative influence on opioid mechanisms. The patients' mean age was 62.5 years, and the average pain intensity was 3.5. The patients' primary opioids were morphine (n=830), oxycodone (n=446), fentanyl (n=699), or other opioids (n=234). Pain intensity, time on opioids, age, gender, performance status, and bone or CNS metastases predicted opioid dose and were included as covariates. The patients were randomly divided into 1 development sample and 1 validation sample. None of 112 SNPs in the 25 candidate genes OPRM1, OPRD1, OPRK1, ARRB2, GNAZ, HINT1, Stat6, ABCB1, COMT, HRH1, ADRA2A, MC1R, TACR1, GCH1, DRD2, DRD3, HTR3A, HTR3B, HTR2A, HTR3C, HTR3D, HTR3E, HTR1, or CNR1 showed significant associations with opioid dose in both the development and the validation analyzes. These findings do not support the use of pharmacogenetic analyses for the assessed SNPs to guide opioid treatment. The study also demonstrates the importance of validating findings obtained in genetic association studies to avoid reporting spurious associations as valid findings. To elicit knowledge about new genes that influence pain and the need for opioids, strategies other than the candidate gene approach is needed.

European Society for Medical Oncology (ESMO) Program for the integration of oncology and Palliative Care: a 5-year review of the Designated Centers' incentive program.

BACKGROUND: In 1999, the National Representatives of European Society for Medical Oncology (ESMO) created a Palliative Care Working Group to improve the delivery of supportive and palliative care (S + PC) by oncologists, oncology departments and cancer centers. They have addressed this task through initiatives in policy, education, research and incentives. As an incentive program for oncology departments and centers, ESMO developed a program of Designated Centers (DCs) for programs meeting predetermined targets of service development and delivery of a high level of S + PC. METHOD: The history, accreditation criteria and implementation of the DC incentive program is described. RESULTS: Since 2004, 75 centers have applied for designation and 48 have been accredited including 34 comprehensive cancer centers (CCCs) in general hospitals and seven freestanding CCCs. Perceived benefits accrued from the accreditation included the following: improved status and role identification of the center, positive impact on daily work, positive impact on business activity and positive impact on funding for projects. CONCLUSIONS: The accreditation of DCs has been a central to the ESMO initiative to improve the palliative care provided by oncologists and oncology centers. It is likely that many other oncology departments and cancer centers already meet the criteria and ESMO strongly encourages them to apply for accreditation.

[Diagnosis and therapy of tumor related pain]. / Diagnose und Therapie von tumorbedingten Schmerzen.

The World Health Organization guidelines for cancer pain therapy from 1986 are still valid. A prerequisite for adequate pain palliation is an exact anamnesis and pain diagnosis. A multimodal, staged therapeutic concept then needs to be formulated according to the requirements of the patient. The pharmacological treatment starts with non-opioids. If pain control remains insufficient, weak opioids are added. In case of persistent pain these are replaced by strong opioids. The availability of new opioids and/or preparations admits a more sophisticated approach to metabolic disorders and specific pain syndromes. Depending on the presenting pain type, co-analgesics might be added.

[Symptoms involving the gastrointestinal tract]. / Symptome des Gastrointestinaltraktes.

Symptoms involving the gastrointestinal tract are very common in patients who require palliative treatment. They can be caused by the patient's underlying (malignant) disease or by the treatment of this disease. Nausea and vomiting as well as constipation are of the utmost importance in this context due both to their frequency as well as their complex consequences. A careful evaluation of the patient's history combined with a few diagnostic procedures will help to provide a treatment which is orientated on pathophysiology.

[Chronic pain syndrome in uorology]. / Chronische Schmerzsyndrome in der Urologie.

Chronic pain of the genital region remains a therapeutic challenge. Among men, symptoms are mainly related to the prostate, bladder and scrotal organs, and among women to the bladder and vagina. Only some of the cases demonstrate pathologic changes of the symptomatic organs requiring specific treatment. Among pain medications, peripheral analgesics are the most suitable. In the case of chronic pain, which can be classified according to Gerbershagen, a psychosomatic origin also has to be considered and needs to be evaluated. Analgesics are of minor importance in the treatment of psychosomatic syndromes but tricyclic antidepressants or anticonvulsants may be helpful. Relaxation techniques also need to be considered.

Toxicity and/or insufficient analgesia by opioid therapy: risk factors and the impact of changing the opioid. A retrospective analysis of 273 patients observed at a single center.

The charts of 273 cancer patients were retrospectively analyzed in order (1) to evaluate the frequency of opioid change (OCH) when adjuvants (antiemetics/laxatives) were administered on a regular basis and co-analgesic medication as indicated by the specific type of pain, (2) to define risk factors for the request of OCH, and (3) to reveal settings in which OCH may not be recommended as a first-line therapeutic intervention. Opioids used included morphine, fentanyl, 1-methadone, and buprenorphine. Out of 273 patients, 103 changed opioids at least once, with a success rate of 65%. The indications for the OCH were insufficient analgesia in 43%, intolerable side effects in 20%, both in 15%, and other reasons in 22% of patients. The frequency of OCH was not influenced by the routine use of adjuvants or co-analgesics except corticosteroids, which raises queries about the concept of an opioid-sparing effect of co-analgesics. The occurrence of intolerable side effects is thought not to be dose dependent so much as to reflect differences in the individual tolerability of a distinct opioid for whatever reason (genetically fixed or individually acquired pharmacodynamic or kinetic properties). Moreover, there was strong evidence for the existence of an unpredictable and incomplete cross-tolerance between opioids, which meant careful titration of the new opioid was required after OCH. The overall frequency of OCH was similar to that observed in previous studies in spite of the documented addition of adjuvants and co-analgesics. This retrospective study supports the notion that opioid rotation must be retained as an essential therapeutic option even with optimized adjuvant and co-analgesic regimens.

Pain and symptom control for cancer patients at the University Hospital in Essen: integration of specialists' knowledge into routine work.

At the University Hospital of Essen, supportive care for patients with cancer and other painful diseases is carried out by an interdisciplinary ambulant pain clinic supported by a pain conference with delegates from all departments involved in the care of cancer patients as permanent members. More than 600 in- and outpatients per year are treated by this institution. This model tends to integrate supportive care into the overall therapeutic concept and routine work and to improve education in this field by bedside teaching and training of local specialists in every department. Therefore, when hospitalization becomes inevitable it is realized within the department mainly concerned with the underlying disease, where the registrar and the physician belonging to the palliative care team work closely together. Scientific research in the field of palliative care, including supportive care, is a further concern of the pain clinic. Evaluation of the model shows that the concept has been realized within a decentralized and interdisciplinary setting; it must, of course, be borne in mind that the staff of the pain control clinic are deeply committed to their work. In conclusion, the way supportive care is realized in Essen can be recommended for large hospitals, and especially for medical schools.

Complications of spinal opioid therapy: myoclonus, spastic muscle tone and spinal jerking.

This study was made in order to define risk factors for patients requiring spinal opioid therapy developing painful spastic muscle tone together with myoclonus and spinal jerking (MSJ). The case histories of 75 patients, all receiving morphine spinally, were retrospectively analysed and, of these, 10 suffered from the MSJ syndrome. The following were taken as evaluation criteria: age, sex, performance status, duration and dosage of previous systemic and current spinal morphine therapy, concomitant analgesic and co-analgesic medication, pretreatment of the dorsal column and neurological dysfunction due to damage either of the nerval plexus or of the medulla spinalis. As a result, high spinal morphine doses in conjunction with pathological changes within the spine were shown to be risk factors for this syndrome. Changing from spinal to systemic morphine application or reduction of spinal doses together with the addition of systemic morphine led to complete recovery from MSJ. As underlying mechanism, an imbalance between the activity of spinal and central opioid receptors and/or toxic morphine effects on the medulla spinalis are discussed. In conclusion, great care should be taken when applying morphine to the spine in patients with neurological dysfunction due to an apparent pathology of the medulla spinalis, especially if large amounts of morphine are likely to be required. Some systemic application of morphine might reduce the risk of patients developing MSJ syndrome.

Anti-depressants and anti-convulsants for the treatment of neuropathic pain syndromes in cancer patients.

20 patients with neuropathic pain syndromes due to tumor-infiltration, who had not responded to conventional analgesics including strong opioids, received additional combination anti-convulsant and anti-depressant treatment. Pain amelioration occurred in all patients within median 46 h, and maximum effect was encountered within one week. Severe side effects were confined to three cases and were associated with carbamazepine treatment. Replacement by another type of anticonvulsants in 6 cases with either no response or intolerable side effects was successful in 5 patients, both in terms of efficacy and tolerability. One patient stopped taking AD/AC after 48 h.