PREPARED IN ASSOCIATION WITH AND PROVIDED AS A SERVICE TO PAIN MANAGEMENT BY MUNDIPHARMA GesmbH
2008: ISSUE 4
Assessment of naloxone to reduce opioid-induced bowel dysfunction Dr Joachim Nadstawek examines this strategy
individuality of pain perception and analgesic effectiveness Reasons for variation in pain perception and drug response are discussed by Dr Jorge Malouf
analgesic prescribing for palliative care patients with renal impairment
A guide by Drs Rachel Sheils and Karen Simpson
Professor Elon Eisenberg Director, Pain Relief Unit,Haifa, Israel
Professor Margarita Puig Director, Anaesthesiology Research Unit, UAB, Barcelona, Spain Dr Annica Rhodin Pain clinician and anaesthesiologist, Uppsala, Sweden Dr Karen Simpson Consultant in anaesthesia and pain management, Leeds, UK
Dr Karen Simpson reviews the best and most interesting international research. Studies include neuropathic pain and chronic Lyme disease. Page 2
Your questions answered
Professor Elon Eisenberg provides the answers to some of your questions. Topics covered include menstrual migraine and ketamine in cancer. Page 7
Dr Ramiro Palazón introduces a case of treating neuropathic pain from spinal cord injury in a patient with psychiatric co-morbidities. Page 10
Dr Ans Vielvoye-Kerkmeer Pain clinician and anaesthesiologist, Leiden, The Netherlands
Prescribing information can be found attached to the back cover and/or on the outside back cover
Download all issues for free. See Page 7 for details of how to register.
A study has investigated the role of genetics in women’s pain perception and relief following Caesarean section. In the Singapore-based study, 588 women were divided into three genotype groups which were found to correlate with significant differences in self-administered morphine consumption following the procedure. www.medicalnewstoday.com/articles/119118.php A US study has found that reported pain relief using smoked cannabis was greater than placebo in HIV patients with neuropathic pain. The proportion of patients achieving pain reduction of 30 per cent or more was greater in the group receiving medicinal marijuana than the placebo group, according to researchers. Existing treatments, including opiates, had proven ineffective for the 28 participants. www.medicalnewstoday.com/articles/117509.php Scientists have identified an enzyme believed to be responsible for endometriosis, the most common cause of pelvic pain in women. Researchers at the University of Liverpool found that telomerase is released in the inner lining of the womb late in the menstrual cycle of women affected by the condition. Telomerase enables cells from the inner lining of the womb to survive elsewhere in the abdominal cavity, causing pain. www.liv.ac.uk/news/press_releases/2008/08/ endometriosis.htm An extract of the herb Boswellia serrata, also known as Indian frankincense, can reduce osteoarthritis symptoms, according to recent research. A randomised, doubleblinded, placebo-controlled trial of 70 patients found significant improvement after seven days, researchers said. The extract was enriched with 30 per cent 3-Oacetyl-11-keto-beta-boswellic acid (AKBA), thought to be the most active ingredient of the plant. http://arthritis-research.com/content/10/4/R85
Next issue... drug interaction in the gut Professors Lars Arendt-Nielsen and Asbjørn Drewes look at new targets for treating visceral pain LAXATIVES WITH OPIOID THERAPY Professor Harald Breivik discusses the impact of pain medication on GI function and the side-effects of conventional laxative therapy.
Research Update Dr Karen Simpson, Consultant in Anaesthesia and Pain Management, Leeds Teaching Hospitals, Leeds, UK, presents the best recently published research papers and reviews Tracey I. Imaging pain. Br J Anaesth 2008;101:32-9. Modern neuroimaging may provide a noninvasive, systems-level understanding of the central mechanisms involved in pain processing. Objective data related to the individual’s pain experience facilitate the understanding of the central mechanisms contributing to chronic pain and give clinicians important diagnostic information. Neuroimaging techniques may identify areas in the neuraxis where plasticity, sensitisation and other amplification processes might occur and may then allow this to be related to the individual’s pain experience. Imaging may allow more objective pain assessment and give clues for more specifically targeted treatments. In future it is likely that functional imaging will move from a research tool to part of everyday practice.
trials to define the role of these techniques in pain management. Zautra AJ, Davis MC, Reich JW, et al. Comparison of cognitive behavioral and mindfulness meditation interventions on adaptation to rheumatoid arthritis for patients with and without history of recurrent depression. J Consult Clin Psychol 2008;76:408-21. Patients are becoming increasingly aware of the potential for psychological therapies to help manage their pain. They often ask about this during consultations and may have researched and downloaded information from the internet themselves. It is therefore important that clinicians have sound research upon which to base their recommendations. This group assessed whether cognitive behavioural therapy and mindfulness inter ventions targeting responses to chronic stress, pain and depression are effective in reducing pain and improving quality of life for adults with rheumatoid arthritis (RA). The researchers recruited 144 people with RA and formed them into groups of six to 10 patients. They randomly assigned patients to one of three treatments: cognitive behavioural therapy for pain (P), mindfulness meditation and emotion regulation therapy (M), or education only (E – this was an attention-placebo control). Those patients receiving P showed the greatest improvement in self-reported pain control and reductions in interleukin (a marker of inflammation). Both the P and M groups showed greater improvement in coping efficacy than the E group. The relative value of the treatments varied as a function of the patients’ history of depression. Those with recurrent depression benefited most from M treatment. Rheumatoid arthritis; SPL
paineurope 2008: Issue 4
Lima MC, Fregni F. Motor cortex stimulation for chronic pain: systematic review and meta-analysis of the literature. Neurology 2008;70:2329-37. The authors conducted a systematic review and meta-analysis to assess the efficacy of invasive and non-invasive brain stimulation for the treatment of chronic pain. They assessed studies that used a visual analogue scale as the pain assessment tool. They included 11 studies using non-invasive brain stimulation and 22 using invasive brain stimulation.The response rate was 73 per cent for invasive stimulation and 45 per cent for non-invasive stimulation; this difference was significant. The authors concluded that the two different types of motor cortex stimulation can exert a significant effect on chronic pain. They ended by highlighting the need for well-designed clinical
Williams JA, Day M, Heavner JE. Ziconotide: an update and review. Expert Opin Pharmacother 2008;9:1575-83. Intrathecal drug delivery (ITDD) can provide excellent analgesia for a small percentage of
patients with non-cancer or cancer-related pain. In addition, ITDD may reduce oral drug sideeffects observed with opioids routinely used to treat chronic pain patients. A novel ITDD drug, ziconotide is a synthetic peptide analogue of conotoxin originally derived from the marine snail, Conus magus. It is a selective, potent blocker of neuronal N-type calcium channels and is able to inhibit inputs from primary nociceptors. Ziconotide is the first analgesic for many years to provide a new mechanism of analgesic action. Ziconotide has to be given intrathecally and also has a narrow therapeutic window which can be managed by appropriate dose titration. The drug appears to be a highly versatile analgesic; however there is an observed individual variability of analgesia achieved. Importantly, no apparent tolerance to ziconotide analgesia has been observed. The authors present the available safety, efficacy and dosing information for ziconotide. They conclude that patients receiving ziconotide should be under the care of physicians experienced in the management of ITDD for pain control and should have convenient and timely access to medical facilities. Bouhassira D, Lantéri-Minet M, Attal N, et al. Prevalence of chronic pain with neuropathic characteristics in the general population. Pain 2008;136:380-7. The authors carried out a nationwide postal survey to estimate the prevalence of chronic pain with or without neuropathic characteristics in the French population. A Douleur Neuropathique 4 questionnaire was sent to 30,155 patients. There was a good return
Further key clinical papers Walker SM.
Pain in children: recent advances and ongoing challenges. Br J Anaesth 2008;101:101-10. Karp JF, Shega JW, Morone NE, et al.
Advances in understanding the mechanisms and management of persistent pain in older adults. Br J Anaesth 2008;101:111-20. Delaney A, Fleetwood-Walker SM, Colvin LA, et al.
Translational medicine: cancer pain mechanisms and management. Br J Anaesth 2008;101:87-94. Tandon S, Sabanegh E Jr.
Chronic pain after vasectomy. BJU Int 2008;102:166-9.
rate (81 per cent, with 97 per cent of the questionnaires returned assessable). Chronic pain prevalence was 32 per cent; in 20 per cent pain was moderate to severe.Neuropathic characteristics were reported by 7 per cent of patients with chronic pain; in 5 per cent neuropathic pain was moderate to severe. As expected, a higher prevalence of chronic pain with neuropathic characteristics was associated with middle age, manual professions and people living in rural areas. Pain was more frequent in the lower limbs and its intensity and duration were higher in comparison with chronic pain without neuropathic characteristics. Macrae WA. Chronic post-surgical pain: 10 years on. Br J Anaesth 2008;101:77-86. Pain after surgery is common and affects the lives of many people who had expected to have surgery and return to relative normality. Dr Macrae reviews how the situation has changed over the past 10 years, during which there has been recognition that chronic postsurgical pain is a significant problem. This is a complex area of research and although the quality of studies has improved many difficulties remain. Several recent publications have examined risk factors.Severe acute postoperative pain emerges as a factor that we may be able to influence. There is a need for greater education in this area for both the medical profession and the general public, so that effective measures are introduced and unnecessary and inappropriate operations minimised. Marques A. Chronic Lyme disease: a review. Infect Dis Clin North Am 2008;22:341-60. Clinicians attempting to diagnose mysterious chronic pain may overlook the possibility of Lyme disease. Studies have shown that most patients diagnosed with chronic Lyme disease either have no objective evidence of previous or current infection with Borrelia burgdorferi or should be classified as having post-Lyme disease syndrome, which is defined as continuing or relapsing nonspecific symptoms (such as fatigue, musculoskeletal pain, and cognitive complaints) in a patient previously treated for Lyme disease. Despite extensive study, there is currently no clear evidence that post-Lyme disease syndrome is caused by persistent infection with B burgdorferi. Antibiotic therapy offers no sustained benefit to patients who have postLyme disease syndrome. The authors present an interesting review of chronic Lyme disease and comment on the need for further research.
Meetings and events update 27–31 January 2009 25th Annual Meeting of the American Academy of Pain Medicine Honolulu, Hawaii, US Telephone: +1 847 375 4731 Email: firstname.lastname@example.org Website: www.painmed.org 13–16 March 2009 5th World Congress of the World Institute of Pain New York, US Telephone: +1 336 714 8385 Email: email@example.com Website: www.kenes.com/wip 31 March–3 April 2009 2009 Annual Scientific Meeting of the British Pain Society London, UK Telephone: +44 20 7269 7840 Email: firstname.lastname@example.org Website: www.britishpainsociety.org/ meet_ASM.htm 20–21 April 2009 3rd national conference: Current Issues in Palliative Care London, UK Telephone: +44 20 7501 6762 Fax: +44 20 7733 8174 Website: www.mahealthcareevents.co.uk 23–25 April 2009 2nd World Congress of Total Intravenous Anaesthesia Berlin, Germany Telephone: +41 22 908 0488 Email: email@example.com Website: www.kenes.com/tiva-tci/index.asp Tick carrier of Lyme disease pathogen; SPL
paineurope 2008: Issue 4
paineurope 2008: Issue 4
Assessment of naloxone to reduce opioid-induced bowel dysfunction Joachim Nadstawek, Clinic of Anaesthesiology and Intensive Care Medicine, University of Bonn, Germany Opioids are an effective analgesic for chronic cancer and non-malignant pain, but their use is frequently associated with chronic constipation which can have a profound impact on a patient’s quality of life. Although other opioid-associated side-effects tend to resolve with longterm use of the drugs, no tolerance appears to develop for constipation. 1 Many patients are forced to either discontinue opioid therapy or reduce the dose taken because of the discomfort and pain of constipation, and this obviously has an adverse impact on their analgesia.2 Constipation is therefore an adverse event that needs to be prevented or treated to ensure patients receive the pain control they need. Laxatives can be used both for the treatment and prevention of opioid-induced constipation, but they are largely ineffective because they do not interfere with opioid receptor binding in the gut which is the cause of constipation.2,3 This binding is not important for the drug’s analgesic effects, which involves opioid receptors in the central nervous system (CNS).2,4
Potential for opioid antagonists The competitive opioid receptor antagonist naloxone is usually administered intravenously to mop up opioid in cases of opioid overdose. 5 However, if administered orally, naloxone can significantly reduce constipation associated with opioids while still allowing them to provide effective analgesia.6 Oral naloxone has the negligible systemic bioavailability of approximately 2 per cent,7 so has an inhibitory effect on opioids in the gut without interfering with receptor binding in the CNS. Furthermore, patients appear to like the approach, finding the combination of opioid and naloxone both effective and tolerable. These findings come from a study of 202 patients with severe cancer or non-cancer pain who attended 28 centres in Germany between May 2002 and April 2003.8 Before entering the study, the patients were stabilised on prolonged release oxycodone (40–80mg per day). Oxycodone is a strong, semi-synthetic opioid used to treat severe chronic pain, including neuropathic pain. The patients involved also had to be constipated, which was defined as needing to take laxatives in order to have three bowel movements per week.
Patients were randomly assigned to one of four intervention groups. Those in the first three groups took 10, 20 or 40mg per day of prolonged release oral naloxone every 12 hours co-administered with their oxycodone for four weeks. The fourth group took a placebo. No dose adjustments to the drugs were allowed and patients were asked not to take laxatives unless they did not have a bowel movement for three days. After four weeks, naloxone was stopped and patients continued to take oxycodone alone for a further two week follow-up period. Patients’ views of the overall efficacy and tolerability of the different doses of naloxone and the placebo were then assessed. Efficacy was considered to be effective pain control and any improvements in bowel function. Both efficacy and tolerability were ranked using the scale: very good; good; fairly good; moderate; slightly poor; poor; and very poor. Both patients and investigators reported that the efficacy of oxycodone improved with increasing the coadministered naloxone dose.The 40mg dose was ranked as ‘good’ or ‘very good’ by 72.5 per cent of patients, the 10mg
Key learning points Constipation is a side-effect of long-term opioid use
that impacts significantly on patients’ quality of life.
Naloxone is a competitive opioid receptor antagonist
which can reduce constipation when taken orally in combination with the opioid oxycodone.
Oral naloxone mops up opioid in the gut, reducing its
ability to cause constipation through binding to opioid receptors in the gut wall.
As oral naloxone has negligible systemic
bioavailability, its does not interfere with opioid binding to receptors in the central nervous system required for analgesia.
Patients prefer co-administered oxycodone and
naloxone to oxycodone alone and the efficacy increases with naloxone dose.
The efficacy of oxycodone plus 40mg naloxone was
ranked ‘good’ or ‘very good’ by 72.5 per cent patients compared with 43.5 per cent who took placebo.
Tolerability of naloxone is similar to that of placebo
regardless of dosage.
The optimal dose ratio of oxycodone to naloxone is 2:1.
paineurope 2008: Issue 4
Figure 1. Patients’ assessment of treatment efficacy
by 50 per cent and the placebo by 43.5 per cent (see Figure 1). Just 17.5 per cent of patients ranked the 40mg naloxone as ‘moderate’ to ‘very poor’ compared with 43.5 per cent of patients taking placebo. Correspondingly, 70 per cent of investigators ranked the 40mg dose as ‘good’ or ‘very good’, 54.8 per cent the 10mg dose and 47.8 per cent the placebo. Naloxone was well tolerated by patients at all the doses assessed. Tolerability of the 40mg naloxone dose was ranked ‘good’ or ‘very good’ by 82.5 per cent of patients and 85 per cent of investigators, while 83.3 per cent of both groups gave the 10mg dose this ranking. The placebo group was considered ‘good’ or ‘very good’ by 71.7 per cent of patients and 78.3 per cent of investigators. Overall, both patients and investigators had a preference for co-administered naloxone and oxycodone over oxycodone alone both in terms of efficacy and tolerability. Another primary aim of the research was to determine the optimal dose ratio for oxycodone and naloxone for analgesic efficacy and bowel function. Within the three naloxone treatment groups, seven active oxycodone/ naloxone dose ratios were evaluated (1:1, 1.5:1, 2:1, 3:1, 4:1, 6:1 and 8:1). The optimal ratio was identified as 2:1.6 The efficacy of the 2:1 dose ratio was ranked ‘good’ or ‘very good’ by 70.4 per cent of patients, while 43.5 percent of patients thought the placebo was this effective. Tolerability of the 2:1 dose ratio was ranked ‘good’ or ‘very good’ by 81.5 per cent of patients, compared with 71.7 per cent for the placebo. Taking naloxone did slightly increase the risk of a patient experiencing an adverse event, and this risk increased with the dose. Adverse events such as sweating, diarrhoea, nausea, abdominal pain, restlessness, muscle cramps, sedation, headache and vertigo were seen in 70 per cent of patients who took the highest naloxone dose (40mg) compared with 62.7 per cent who took the placebo.
Implications for practice Overall, the addition of prolonged release naloxone to prolonged release oxycodone improves patients’ assessment of their analgesic therapy and most say they
prefer it to oxycodone alone. Patients found oxycodone was more effective when naloxone was co-administered, while the tolerability of the therapy remained similar, indicating that the benefits of taking naloxone to reduce constipation are not offset by it causing a large number of other adverse events. Naloxone seems to be a useful addition to therapy for improving the analgesic efficacy of oxycodone while significantly reducing the impact of opioid-induced constipation by increasing stool frequency and decreasing use of laxatives.7 Constipation is the most frequently reported adverse event associated with chronic opioid therapy,9 and prevention of this adverse event is a better and more effective therapeutic strategy than treating constipation once it occurs.2 As oxycodone is effective for a variety of chronic pain conditions, including cancer, non-cancer and neuropathic pain, the addition of naloxone to prevent or reduce opioidinduced constipation could benefit a significant number of patients and increase their quality of life. Co-administering naloxone/oxycodone allows patients to receive effective and adequate long-term pain relief with less risk of them having to experience painful and distressing opioid-induced constipation as a result. References 1. Ballantyne JC. Opioid analgesia: perspectives on right use and utility. Pain Physician 2007;10:479-91. 2. Kurz A, Sessler DI, Opioid-induced bowel dysfunction: pathophysiology and potential new therapies. Drugs 2003;63:649-71. 3. Pappagallo M. Incidence, prevalence, and management of opioid bowel dysfunction. Am J Surg 2001;182(Suppl 5A):S11-8. 4. Holzer P. Opioids and opioid receptors in the enteric nervous system: from a problem in opioid analgesia to a possible new prokinetic therapy in humans. Neurosci Lett 2004;361:192-5. 5. Choi YS, Billings JA. Opioid antagonists: a review of their role in palliative care, focusing on use in opioid-related constipation. J Pain Symptom Manage 2002;24:71-90. 6. Meissner W, Leyendecker P, Mueller-Lissner S, et al. A randomised controlled trial with prolonged-release oral oxycodone and naloxone to prevent and reverse opioid-induced constipation. Eur J Pain. 2008. [Epub ahead of print]. 7. Liu M, Wittbrodt E. Low-dose oral naloxone reverses opioid-induced constipation and analgesia. J Pain Symptom Manage 2002;23:48-53. 8. Nadstawek J, Leyendecker P, Hopp M, et al. Patient assessment of a novel therapeutic approach for the treatment of severe, chronic pain. Int J Clin Pract 2008;62:1159-67. 9. Coluzzi, F, Pappagallo M. Opioid therapy for chronic noncancer pain: practice guidelines for initiation and maintenance of therapy. Minerva Anestesiol 2005;71:425-33.
6 IN MY OPINION
paineurope 2008: Issue 4
Biological factors in patient response
Individuality of pain perception and analgesic effectiveness Dr Jorge Malouf, Internal Medicine Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
morphisms are probably those encoding the μ-opioid receptor (MOR), the primary binding site for opioid analgesics.The most common SNP is A118G which exchanges an amino acid at position 40 from asparagine to aspartate, implying a 3.5-fold higher affinity for β-endorphin, but not for other opioids.4 Multiple alternative spliced variants and promoters for the mouse MOR-1 (Oprm) have been described. The Exon-1 promoter was the first promoter to be described and drives transcription of 16 splice variants. These variants show binding affinities that are similar to their identiBehavioural/cognitive approach δ-opioid receptor subtype 1 gene have a Positron emission cal binding pockets, nevertheless μ-opioid Some human studies suggest that the higher threshold to cold-pressor pain tomography scan of potencies and efficacies vary among the administration of dopamine agonists than the combined heterozygous– the brain responding MOR-1 variants.10–13 reduces pain ratings in some painful homozygous wild-type group.3 to pain syndromes, while other studies have found Conclusion a direct association between the Encephalic bioavailability All the biological differences explained administration of dopamine antagonists Other important factors that are reported in this short review help us to understand and the reduction of pain scores. to influence the response to opioid the diversity we usually see in pain and In an attempt to explain these analgesics occur as a result of molecular analgesia. It is therefore important to contradictions, a study by Scott et al alterations at the level of drug transport rotate opioids if we see toxicity or poor revealed dopamine D2 receptor proteins and hepatic enzymes. The ATPresponse to our first choice, or maybe activation secondary to pain, involving binding cassette B1 (ABCB1)/multiple even combine low doses of different the dorsal and ventral ganglia regions.2 drug resistance 1 (MDR1) gene has been opioids. Dorsal caudate and putamen dopamine considered a factor in the encephalic Further pharmacogenetic studies are activity correlated positively with pain bioavailability of many opioids.4, 5 Wang et needed to completely understand all the scores and pain quality, whereas the al showed that the SNP C3435T clearly mechanisms that generate the interincrease in the activation of dopamine affects expression and function onABCB1/ patient differences in pain perception activity in the ventral, mesolimbic region MDR1 gene, accounting for a 1.5–2-fold and response to drugs. was associated with greater variation in difference in the expression of mRNA.6 References the experience of pain between 1. Aubrun F, Langeron O, Quesnel C, et al. Anesthesiology 2003;98:1415-21. individuals. Dopamine activity may thus Hepatic metabolic enzymes 2. Scott DJ, Heitzeg MM, Koeppe RA, et al. J also play a role in individual differences The systemic bioavailability of many Neurosci 2006;26:10789-95. 3. Kim H, Neubert JK, San Miguel A, et al. Pain in pain perception. medications may be altered by hepatic 2004;104:488-96. metabolic enzymes. Four to 10-fold 4. Somogyi AA, Barratt DT, Coller JK. Clin Pharmacol Ther 2007;81:429. Genetic approach differences in oxycodone bioavailability Dr Jorge Malouf: why 5. Campa D, Gioia A, Tomei A, et al. Clin Pharmacol Ther 2007;83:559-66. Vanilloid and δ-opioid receptors by enzyme activity (O-demethylation of are there such 6. Wang D, Sadée W. AAPS J 2006;8:E515-20. Genetic polymorphisms may largely oxycodone to oxymorphone) in humans marked differences 7. Rogers JF, Nafziger AN, Bertino JS. Am J Med 2002;113:746-50. account for the observed inter-individual have been identified. Variability in in patients’ 8. Kadiev E, Patel V, Rad P, et al. Expert Opin Drug Metab Toxicol 2008;4:77-91. variation in pain relief and tolerance. Kim response to other opioids has been linked responses to 9. Crettol S, Deglon JJ, Besson J, et al. Clin Pharmacol et al reported that variants of a vanilloid to other CYP 450 enzymes: CYP2D6 treatment with Ther 2005;78:593-604. 10. Uhl GR, Sora I, Wang Z. Proc Natl Acad Sci receptor subtype-1 gene provide a (codeine and tramadol), CYP3A5 opioid analgesics? U S A 1999;96:7752-5. 11. Rossi GC, Leventhal L, Pan YX, et al. J Pharmacol different cold-pressor tolerance time.3 (fentanyl) and CYP2B6 (methadone).7–9 Exp Ther 1997;281:109-14. That same study provides evidence that 12. Pan YX, Xu J, Mahurter L, et al. Proc Natl Acad Sci USA 2001;98:14084-9. carriers of heterozygous T80G single- The μ-opioid receptor 13. Pan YX, Xu J, Bolan E, et al. FEBS Lett 2000;466:337-40. nucleotide polymorphism (SNP) of the The most important genetic poly
Although all opioids act mainly on the same receptor for their analgesic action, there are striking differences in their analgesic effect, tolerance and sideeffects. In a study involving more than 3,000 patients,the morphine requirements for postoperative pain varied almost 40fold among patients.1 Since pain is an interaction of activation, transmission and suppression of many systems, there should be many different reasons for individual perception and therefore individual treatment.
paineurope 2008: Issue 4
DISCUSSION FORUM questions and answers Professor Elon Eisenberg answers some of your
common questions about pain management. Email your questions to firstname.lastname@example.org
What are the most effective strategies for treating menstrually related migraine? The International Classification of Headache Disorders, second edition, defines menstrually related migraine as attacks that occur on day -2 to +3 of menstruation in at least two of three menstrual cycles.1 The first day of the menstrual cycle is defined as day 1, and the day preceding menstruation is day -1. Menstrually related migraine is not uncommon, and may occur in 8 per cent of women. These migraine attacks are commonly viewed as having longer duration and being more severe and more refractory to treatment than non-menstrually related migraine attacks. The treatment of menstrually related migraine is divided into two strategies: Abortive therapy taken at the time of the migraine. Short-term prevention taken perimenstrually. According to a recent evidence-based metaanalysis,2 the following agents have been recommended for acute abortive treatment of menstrually related migraine: sumatriptan 50– 100mg, rizatriptan 10mg or a three-times-daily dose of mefenamic acid 500mg, starting at onset of the perimenstrual migraine. For short-term prevention, the perimenstrual use of estradiol gel 1.5mg, frovatriptan 2.5mg twice daily or naratriptan 1mg twice daily have been recommended. Preventive treatment should be initiated a few
days prior to the expected migraine attack and last for about six days. 1.
Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalagia 2004;24 Suppl 1:9-160.
Pringsheim T, Davenport WJ, Dodick D. Acute treatment and prevention of menstrually related migraine headache: evidence-based review. Neurology 2008;70:1555-63.
A 67-year-old woman underwent abdominoperineal resection for rectal cancer, which was followed by radiation therapy. About four months later she developed excruciating, burning pain in her perineum and along her right leg. A CT scan revealed a pre-sacral mass. How should this patient be managed? This patient presents significant diagnostic and therapeutic challenges. Diagnostically the patient seems to have primarily (although not necessarily exclusively) neuropathic pain. Completing a formal neuropathic pain questionnaire (such as painDETECT, Douleur Neuropathique 4 or the self-administered Leeds Assessment of Neuropathic Symptoms and Signs test), conducting a careful neurological examination and, if necessary, performing electromyography with nerve conduction tests are likely to establish the diagnosis of neuropathic pain. The second diagnostic question is, what causes this pain? The combination of sacral neuropathic pain syndrome and a pre-sacral mass revealed by CT leads to the following differential diagnoses:
Invasion of tumour into the sacral plexus. Non-malignant fibrous (scar) tissue in a
previously operated/irradiated area involving the sacral plexus. Notably, spine metastases involving the conus medullaris/cauda equina should also be ruled out. A correct diagnosis is essential for determining if further anti-tumour therapy is indicated. Tumour markers can give a good indication of the presence of active disease. Imaging studies such as an MRI with or without contrast and/or PET-CT can be informative but are not always conclusive. Tissue biopsy should also be considered. Since advanced imaging studies are not readily available everywhere and may require considerable time to complete, analgesic treatment should begin immediately. The neuropathic characteristics of the pain and its severity justify use of a combination of an opioid and an adjuvant drug (such as an anticonvulsant or antidepressant), both aggressively up-titrated. If the diagnosis of tumour invasion into neural tissue is established, a trial of steroids can be considered. In this case, an anti-tumour therapy is likely to be added also.
Is there a role for ketamine in the management of cancer pain? An increasing number of reports, including a few small, randomised, controlled trials suggest that ketamine can be helpful for cancer patients with breakthrough pain, neuropathic pain or pain resistant to high-dose opioids. Ketamine is administered via continuous IV, intranasal, sublingual, oral and intrathecal routes. However, ketamine is still regarded as an adjuvant therapy and should be used cautiously for selected patients with refractory pain.1 Sideeffects include nausea, vomiting, dizziness, and emotional distress. Potential neurotoxicity with chronic neuroaxial administration precludes recommendation for long-term intrathecal administration of ketamine. 1.
Ben-Ari A, Lewis MC, Davidson E. Chronic administration of ketamine for analgesia. J Pain Palliat Care Pharmacother 2007;21:7-14.
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paineurope 2008: Issue 4
Analgesic prescribing for palliative care patients with renal impairment Dr Rachel Sheils, Specialist Registrar in Palliative Medicine and Dr Karen H Simpson, Consultant in Anaesthesia and Pain Management, Leeds Teaching Hospitals, Leeds, UK
be adjusted for palliative care patients with renal impairment to provide effective pain relief.
Kidney dialysis; SPL
Tailoring treatment to individual need
Analgesic prescribing can be adjusted for palliative care patients with renal impairment to ensure effective pain relief Palliative care professionals recognise the importance of renal impairment when prescribing for patients who often have multiple problems as well as cancer. In the UK, the Department of Health and the Marie Curie Palliative Care Institute have published guidelines for prescribing in advanced chronic kidney disease for those patients in the last days of life.1 Patients with renal impairment in the palliative care population fall into a number of groups: P Chronic kidney disease is the life-limiting illness. P Renal impairment is a complication of the life-limiting illness (eg ureteric obstruction in intra-abdominal cancer). P Treatment of the life-limiting disease has caused renal impairment (eg anti-cancer chemotherapy or diuretic use in end-stage heart failure). P Renal impairment has resulted from palliation of the life-limiting illness (eg from NSAIDs used for pain management). Given the range of analgesics available and knowledge of their varied pharmacokinetics, analgesic prescribing can
Changes to the drug used, the dose or the interval of administration will depend on the severity of renal impairment in each case. Up to 50 per cent of kidney function can be lost before the patient’s creatinine concentration becomes abnormal. A better marker of renal drug clearance is the glomerular filtration rate (GFR). This is measured in some people receiving chemotherapy, for example, by inulin clearance testing. However, this test would be too burdensome for many palliative care patients, so GFR is usually estimated in this group. The CockcroftGault equation, which accounts for the patient’s weight, is the preferred method when using GFR for adjusting drug prescribing.2 Normal GFR is >90ml/min/ 1.73m 2 (body total surface area).2 When prescribing regular opioids, especially sustainedrelease formulations, the drug may accumulate, causing adverse effects such as ventilatory depression. If these are not recognised and treated, premature death may occur. When using (usually short-acting) opioids, if the drug is not cleared, eg because of renal impairment, its analgesic effects will continue. It is therefore essential to allow increased intervals between doses in these circumstances, to reduce the risk of opioidrelated adverse events. It is also important to note that the sedating properties of any drug can be exaggerated in patients with renal impairment due to the increased permeability of the blood–brain barrier. The symptom burden in patients with advanced chronic kidney disease is comparable to that in terminal malignancy.3 The principle of preventing pain recurring by the use of regular analgesia still applies to this group, ie analgesics by the clock rather than as required.4 A careful balance should be established by good pain assessment, effective prescribing and supervision of medication use, especially during initiation and dose increases. Monitoring and managing side-effects is vital in
‘The sedating properties of any drug can be exaggerated due to the increased permeability of the blood– brain barrier as a result of renal impairment
paineurope 2008: Issue 4
Table 1. Dose recommendations for gabapentin and pregabalin in patients with renal impairment GFR (ml/min)
300mg alternate days
300mg twice daily
25mg once daily
25–50mg once daily (or two divided doses)
75mg daily (two to three divided doses)
75mg once daily
150mg once daily (or two divided doses)
300mg daily (two to three divided doses)
patients with renal compromise in order to optimise analgesia and minimise risks.
Opioids Morphine and one of its active metabolites, morphine-6glucuronide, are largely renally excreted. These begin to accumulate once GFR drops to 50ml/min. 5 In some patients, serum creatinine may only just be starting to rise at this stage, highlighting the importance of estimating GFR rather than relying on creatinine when adjusting medication. If morphine is being used purely as needed and the patient’s care is overseen by experienced opioid prescribers then its safe use could continue. It is possible to reduce the regular dose of morphine or increase the dosing interval. However, there is still the potential for opioid accumulation. This is especially true if pain is not stable or if the patient is not supervised by specialist staff. In these circumstances it might be prudent to switch to an opioid with less potential for accumulation. Fentanyl patches can be used without significant fentanyl accumulation if the GFR is above 20ml/min.5 About 20 per cent of oxycodone is renally excreted. More than half of its active metabolites (noroxycodone and oxymorphone) rely on renal clearance, so it can be used regularly without the risk of clinically significant accumulation until the GFR falls to 10mg/ml – beyond this threshold its use is not recommended.5 Hydromorphone and some of its active metabolites are renally excreted; a dose reduction is recommended for GFRs below 20ml/min. 5 Although hydromorphone is not contraindicated when GFR is less than 10ml/min, great care is needed if using this drug in patients with this degree of renal compromise. For those patients with GFRs below 10ml/min, subcutaneous alfentanil can be given via a syringe driver as only 1 per cent is excreted unchanged in urine.5 However, the analgesia derived from as needed subcutaneous alfentanil may be too brief; it can last as little as 30 minutes. In this situation, oxycodone is sometimes used as needed, paying attention to signs of overdose. Buprenorphine patches may also be used with very low risk of symptomatic accumulation in renal impairment as only 1 per cent of the drug is excreted unchanged in urine.5 Although its metabolite norbuprenorphine is partially renally cleared, it is only weakly active.
Methadone relies on hepatic and faecal clearance and thus does not accumulate in renal failure.6 However, despite the fact that methadone is a good analgesic, conversion from other opioids is sometimes avoided in the palliative care population; this may be because of potential difficulties in finding an appropriate dose.5
Antineuropathic drugs Antidepressants are frequently used for patients with neuropathic pain. The commonest drug is amitriptyline; 10 per cent is excreted unchanged in urine. While normal doses of amitriptyline are recommended for those with renal impairment, caution should be exercised because there is an increased potential for sedation in patients with renal failure, independent of drug accumulation.7 The other common group of drugs used for neuropathic pain is anticonvulsants. Only 2 per cent of carbamazepine and 5 per cent of sodium valproate is excreted unchanged in the urine,5 so the same principles apply as for amitriptyline. However gabapentin and pregabalin are 90 per cent renally excreted, so the recommended doses of gabapentin vary with GFR (see Table 1).
NSAIDs As a group, NSAIDs can be nephrotoxic and should be used with extreme caution, particularly in patients with moderate to severe renal impairment. When GFR is less than 10ml/min NSAIDs are usually avoided, unless the patient is dialysed. However, they are sometimes used in palliative care when the alternatives have been ineffective, especially in the last days of life. References 1.
DoH Renal NSF Team and Marie Curie Palliative Care Institute. Guidelines for LCP prescribing in advanced chronic kidney disease. London: The Stationery Office; 2008. 2. Devaney A, Ashley C, Tomson C. How the reclassification of kidney disease impacts on dosing adjustments. Pharm J 2006;277:403-4. 3. Murtagh FE, Addington-Hall JM, Edmonds PM, et al. Symptoms in advanced renal disease: a cross-sectional survey of symptom prevalence in stage 5 chronic kidney disease managed without dialysis. J Palliat Med 2007;10:1266-76. 4. WHO. Cancer Pain Relief. 2nd ed. Geneva: WHO; 1996. 5. Ashley C, Currie A, editors. The Renal Drug Handbook. 2nd edition. Oxford: Radcliffe Medical Press; 2004. 6. Ashley C, Currie A, editors. The Renal Drug Handbook. 3rd edition. Oxford: Radcliffe Medical Press; 2008. 7. Amitriptyline. SPC. 2008. Available from: www.emc.medicines.org.uk. 8. Neurontin (gabapentin). SPC. 2008. Available from: www.emc. medicines.org.uk. 9. Lyrica (pregabalin). SPC. 2008. Available from: www.emc.medicines. org.uk.
10 CASE STUDY
paineurope 2008: Issue 4
Neuropathic pain control Dr Ramiro Palazón, rehabilitation department, National Hospital for Paraplegics, Toledo, Spain Chronic pain is one of the principal problems of patients with spinal cord injury (SCI), with an estimated prevalence of 65–80 per cent among these patients, and a predominance of neuropathic pain over nociceptive pain, which increases over time after the SCI has been sustained.1 According to the International Association for the Study of Pain’s taxonomy, SCI pain is divided into nociceptive or neuropathic, and the neuropathic type is then subdivided into above-level, at-level and belowlevel pain with reference to the level of injury.2 In SCI, neuropathic pain is usually treated following the guidelines available for neuropathic pain of peripheral origin, since the majority of studies on the condition have been conducted on postherpetic and diabetic neuropathy. There are no specific clinical trials on SCI with any drug except pregabalin. The guidelines and recommendations, by level of evidence, include antidepressants, anti-epileptics and opioids as drug treatments for neuropathic pain.3 Traditionally, it has been considered that opioids do not have a significant effect on neuropathic pain, and so treatment of the condition is usually associated with the other two groups of drugs. However, recent studies have demonstrated the efficacy of opioids when used alone.4 Opioids considered to be useful in neuropathic pain are tramadol and oxycodone; their efficacy in neuropathic pain is supported by significant studies.3, 4 Oxycodone acts against neuropathic pain via the µ‑receptors and probably k-receptors. It is used at a dose of 10–99mg per day and is effective, with a NNT of 2.6. Its main side-effects are bowel dysfunction, nausea and, to a lesser extent, sedation.3,5 There are fewer side-effects when it is used in its controlled-release form, even in comparison to other opioids.5
Case assessment This is a case report of a 30-year-old woman, with a history of obsessive-compulsive disorder treated with clomipramine and three attempts at self-harm (overdose with antidepressants), who fell from a sixth floor in another attempt at self-harm. Multiple trauma included L1 vertebral fracture with bulging posterior wall and spinal cord injury. After stabilising the patient haemodynamically and treating visceral injuries for two months, she was then transferred to the National Hospital for Paraplegics, where she underwent arthrodesis from T11 to L3 using the Universal Spine System. She was diagnosed with transverse spinal cord injury syndrome – classified according to the American Spinal Injury Association (ASIA) system as T12 ASIA C – and commenced comprehensive rehabilitation. Since her admission, she referred to mixed pain: mechanical and post-traumatic pain at a lumbar and rib level (visual analogue scale [VAS] 5), and below-level neuropathic pain described as burning and electric discharges to her legs (VAS baseline 5, paroxysms 8). She had been treated with ketorolac and fentanyl in patches, and this, together with the fact that intestinal re-education had not been commenced, caused severe paralytic ileus. Intestinal cleaning was performed and an oral and rectal bisacodyl
Coloured MRI of spinal cord injury; SPL
regimen was commenced in association with lactulose (to treat the neurogenic intestine). She was started on gabapentin, reaching a dose of 800mg/eight hours. Although the fentanyl was withdrawn to begin with in order to treat the intestine, tramadol retard 100mg/12 hours was prescribed in view of its mixed analgesic effect and as an affective disorder regulator, and the VAS score came down by one point. When the patient started standing and walking, there was exacerbation of the mechanical lumbar pain. This was treated with pulsating electrotherapy and kinesitherapy. Paroxysms were treated with clonazepam at up to 1mg/eight hours (the VAS score fell to 4 and the frequency of paroxysms fell from over 15 per day to less than five). Duloxetine at up to 60mg/day was added, and as a result the baseline VAS score was stabilised at 3. As the patient had regular bowel movements by that time, and was almost laxative-free, the treatment was completed with oxycodone (OxyContin® tablets), reaching a dose of 15mg/12 hours, obtaining a baseline VAS score of 1–2, and a paroxysm score of 2, with a frequency of two to three per week. Therefore, this is a case of neuropathic pain that has been treated with first-line drugs as recommended: first a membrane-stabilising anti-epileptic (gabapentin), then a dual serotonin-noradrenaline reuptake inhibitor antidepressant (duloxetine) and finally a strong opioid. The choice of drugs was determined by the patient’s characteristics, chiefly the neurogenic intestine related to the spinal cord injury itself, and the affective disorders. References 1. Siddall PJ, McClelland JM, Rutkowski SB, et al. A longitudinal study of the prevalence and characteristics of pain in the first years following spinal cord injury. Pain 2003;103:249-57. 2. Siddall PJ, Yezierski RP, Loeser JD. Pain following spinal cord injury: clinical features, prevalence and taxonomy. IASP Newsl 2000;(3):3-7. 3. Attal N, Cruccu G, Haanpää M, et al. EFNS guidelines on pharmacological treatment of neuropathic pain. Eur J Neurol 2006;13:1153-69. 4. Furlan AD, Sandoval JA, Mailis-Gagnon A, et al. Opioids for chronic noncancer pain: a meta-analysis of effectiveness and side effects. CMAJ 2006;174:1589-94. 5. Riley J, Eisenberg E, Müller-Schwefe G, et al. Oxycodone: a review of its use in the management of pain. Curr Med Res Opin 2008;24:175-92.
CASE STUDY 11
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in spinal cord injury The Netherlands Dr Ans Vielvoye-Kerkmeer Department of palliative care, St Elisabeth care home, Leiden
Dr Palazón draws our attention to a very complicated problem in the treatment of pain, the control of neuropathic pain in spinal cord injury. The case is much more complex because of the known psychiatric disorder of the patient. Reading this sad history I wonder: P If complete recovery of spinal cord function can be expected and if this issue was discussed with the patient. P What is the patient’s mental state and its impact on her perception of pain. Is any psychological help available? Emotional upset and stress are situations which can cause bowel dysfunction. Dr Palazón is right to point the treatment of neuropathic pain towards the most important groups of drugs – anticonvulsants, antidepressants and opioids. Regarding the reduction in VAS score by one point, following treatment with gabapentin and tramadol, I would then raise the daily dose of gabapentin to
This case is of a 30-year-old woman with obsessive-compulsive disorder, treated with clomipramine, and three attempts of overdose with antidepressants. The patient sustained multiple trauma, including transverse spinal cord injury from an L1 fracture after falling from the sixth floor of a building. The fracture was treated with T11–L3 arthrodesis. After the initial period of treatment for multiple trauma, she had mechanical and post-traumatic pain at a lumbar and a rib level and central neuropathic pain below level of injury. This implies that the patient has both nociceptive and neuropathic pain. The nociceptive pain was treated with transdermal fentanyl and an NSAID that could be gradually withdrawn and substituted with tramadol. The central neuropathic pain was still a problem. However, tramadol in combination with tricyclic antidepressants is problematic, because of the
Pain is one of the main
complications in spinal cord injuries. Only pregabalin has been
3,600mg and the dose of tramadol to 400mg daily. Transdermal fentanyl, a μ-receptor agonist, was started because the patient had a paralytic ileus and fentanyl has a tendency to cause less bowel dysfunction than morphine. However, bowel function did not improve using fentanyl patches. When bowel movements were normal and analgesia was still necessary, the choice was made for oxycodone. The switch from fentanyl to oxycodone was based on patient and drug characteristics. Oxycodone, a μ-, δ- and κ-receptor-agonist has a tendency to cause less confusion and has a good effect on abdominal and neuropathic pain. As with all μ-agonist opioids there is no maximum dose for oxycodone.Neuropathic pain is one of the main complications in spinal cord injuries. Bowel dysfunction is the most significant side-effect of opioids. Over the last 25 years, experimental regimens have found oral naloxone to be effective in small doses. Methylnaltrexone is available in some countries. It has to be given every second day subcutaneously and is self-administered. It is expensive. In my experience, oral naloxone is an easy, effective solution.
Sweden Dr Annica Rhodin Pain clinician and anaesthesiologist Uppsala, Sweden
Key learning points
assessed in clinical trials on treating neuropathic pain in spinal cord injuries. As the spinal cord injury
progresses, neuropathic-type pain predominates. Neuropathic pain is treated
with antidepressants and anti-epileptics, but several studies have shown opioids offer a good therapeutic choice. Tramadol is considered to
be a first-line treatment for neuropathic pain. Neurogenic intestine can
be a determinant factor in the use of opioids in spinal cord injuries, but it can be resolved with suitable treatment. Psychiatric co-morbidities
risks of drug interaction and of developing serotonin syndrome. The line of treatment that we would suggest for central neuropathic pain is the substitution of clomipramine for duloxetine 30–60mg daily; that will have an effect on both the psychiatric problem and the neuropathic pain. Moreover, there is an indication for pregabalin in doses titrated to pain relief, with minimal sideeffects. If that is not sufficient to give adequate pain relief, there is an indication for a strong opioid. The first opioid to consider would be prolonged-release oxycodone, also in titrated dosing. If the analgesic effect is insufficient or there are problems with tolerance, which could be the case in a patient with a psychiatric disorder, methadone could be an alternative. Methadone has a broad mechanism of action, especially in terms of its N-methyl-D-aspartateblocking effect, that can be of particular advantage in neuropathic pain. Also, there is a decreased risk of tolerance with methadone than other strong opioids in long-term treatment.
should have an impact on treatment choice. Emotional upset and
stress can cause bowel dysfunction independent of pharmacotherapy. Transdermal fentanyl tends
to have fewer GI side-effects than morphine. Switching from one opioid
to another should be based on patient and drug characteristics. Oral naloxone and
subcutaneous methylnaltrexone, where available, are effective in treating opioid-induced bowel dysfunction.
Published by Medical Imprint, 174 Hammersmith Road, London W6 7JP. Email: email@example.com. Web: www.paineurope.com. Tel: +44 20 8267 4572. Prepared in association with and supported by Mundipharma International Limited, Cambridge Science Park, Milton Road, Cambridge CB4 OGW, UK. To register for regular copies or apply for further copies of this issue, please contact Mundipharma GesmbH, Apollogasse 16–18, Postfach 83, 1070 Wien, Austria. Managing editor: Bettina Vine; Project editor: Becki Davies; Sub-editors: Gina Lyons, Philip MacDonald; Commercial director: Sandie Pears; Account support administrator: Suzanne Richards; Senior production controller: Nicola Goodman; Group production manager: Philip Root; Group art editor: Pauline Lock; Editor-in-chief: Colin Cooper; Publisher: Richard Yarwood; Managing director: Peter Welland. The views expressed in this publication are those of the authors and not necessarily those of Medical Imprint, the joint editors, Mundipharma International Limited, or its independent associated companies. Readers are advised to make their own further enquiries of manufacturers or specialists in relation to particular drugs, treatments or advice. The sponsor, publisher, editorial board, printer and their respective employees, officers and agents cannot accept liability for errors or omissions. No part of this publication may be reproduced in any form without the written permission of the publisher, application for which should be Haymarket is certified by BSI to environmental standard ISO 14001 made to the publisher. ©2008 Haymarket Medical Media Limited. Not for resale. Date of preparation: December 2008. Item code UK/MIS-08116.
Prescribing information Presentation: Film coated, modified release tablets containing oxycodone hydrochloride, marked OC on one side and the strength of oxycodone hydrochloride on the other. The 10 mg tablets are white and contain 9.0 mg of oxycodone as 10 mg oxycodone hydrochloride. The 20 mg tablets are pink and contain 18.0 mg of oxycodone as 20 mg oxycodone hydrochloride. The 40 mg tablets are yellow and contain 36.0 mg of oxycodone as 40 mg oxycodone hydrochloride and the 80 mg tablets are green and contain 72.0 mg of oxycodone as 80 mg oxycodone hydrochloride. Indications: For the treatment of severe pain. Dosage and administration: OxyContin® tablets must be swallowed whole and are not to be broken, chewed or crushed. Taking broken, chewed or crushed OxyContin® tablets leads to a rapid release and absorption of a potentially fatal dose of oxycodone. Adults and the elderly: OxyContin® tablets should be taken at 12-hourly intervals. The dosage is dependent on the severity of the pain, the patient’s previous history of analgesic requirements, the patient’s body weight, and sex (higher plasma concentrations are produced in females). The usual starting dose for debilitated elderly patients, opioid naive patients or patients presenting with severe pain uncontrolled with weaker opioids is 10 mg 12-hourly. The dose should then be carefully titrated, every day if necessary, to achieve pain relief. Increases should be made, where possible, in 25% - 50% increments. The correct dosage for any individual patient is that which controls the pain and is well tolerated, for a full 12 hours. The need for escape medication more than twice a day indicates that the dosage of OxyContin® tablets should be increased. Adults under 18 years and children: Not recommended. Contra-indications: Respiratory depression, head injury, paralytic ileus, acute abdomen, delayed gastric emptying, severe obstructive airways disease, severe bronchial asthma, hypercarbia, known sensitivity to oxycodone, morphine or other opioids, acute hepatic disease, concurrent administration of monoamine oxidase inhibitors or within 2 weeks of discontinuation of their use. The safety of OxyContin® used pre-operatively and for up to 24 hours post-operatively has not been established and cannot be recommended. Special warnings and precautions for use: As with all narcotics, a reduction in dosage may be advisable in hypothyroidism. Use with caution in opioid dependent patients, patients with toxic psychosis and in patients with raised intracranial pressure, hypotension, hypovolaemia, diseases of the biliary tract, pancreatitis, inflammatory bowel disorders, prostatic hypertrophy, adrenocortical insufficiency, acute alcoholism, chronic renal and hepatic disease, and debilitated patients. OxyContin® tablets should not be used where there is a possibility of paralytic ileus occurring. Should paralytic ileus be suspected or occur during use, OxyContin® tablets should be discontinued immediately. As with all opioid preparations, patients who are to undergo cordotomy or other pain relieving surgical procedures should not receive OxyContin® tablets for 24 hours before surgery. If further treatment with OxyContin® tablets is then indicated the dosage should be adjusted to the new post-operative requirement. As with all opioid preparations, OxyContin® tablets should be used with caution following abdominal surgery as opioids are known to impair intestinal motility and should not be used until the physician is assured of normal bowel function. Pregnancy and lactation: OxyContin® tablets are not recommended for use in pregnancy. Oxycodone is secreted in breast milk and may cause respiratory depression in the newborn. OxyContin® tablets should, therefore, not be used in breast-feeding mothers. Side effects: Adverse drug reactions are typical of full opioid agonists, and tend to reduce with time, with the exception of constipation. Anticipation of adverse drug reactions and appropriate patient management can improve acceptability. The most commonly reported adverse reactions are nausea and constipation, both occurring in approximately 25 to 30 % of patients. If nausea, or vomiting are troublesome, oxycodone may be combined with an antiemetic. Constipation should be anticipated as with any strong opioid, and treated appropriately with laxatives. Should opioid related adverse events persist, they should be investigated for an alternative cause. Tolerance may occur in patients treated with OxyContin®, although this has not been a significant problem in the clinical trial programme. Patients requiring marked dose escalation should have their pain control regimen carefully reviewed. Abrupt withdrawal of OxyContin® tablets or administration of an opioid antagonist may result in a withdrawal syndrome characterised by anxiety, irritability, chills, hot flushes, piloerection, joint pain, rhinorrhea, diaphoresis, abdominal cramps and diarrhoea. If the dose reduction regimen recommended in Section 4.4 results in a withdrawal syndrome, the dose should be slightly increased until the signs and symptoms disappear. Dose reduction should then begin again with longer periods of time between each reduction. Signs of oxycodone toxicity and overdosage are pin-point pupils and respiratory depression. Shelf life: Three years Package quantities: PVC blister packs with aluminium foil backing containing 28, 30, 56 or 60 tablets. Market Authorisation holder: MUNDIPHARMA Ges.m.b.H., Vienna, Austria. ®: OxyContin is a registered trade mark.
oxycodone hydrochloride prolonged release tablets OxyContin速 is a strong opioid