COMPASS Therapeutic Notes on the use of Strong in Chronic Non-Cancer Pain

Glossary of terms In this issue: Hyperalgesic A paradoxical phenomenon whereby a patient receiving treatment for Page syndrome pain may actually become more sensitive to certain painful stimuli Introduction and background 1 MHRA Medicines and Healthcare products Regulatory Agency Strong opioids in common use 2 Neuropathic pain Pain due to disturbance of the nervous system Less commonly used opioids 4 NNT Number Needed to Treat Adverse effects of opioids 4 Nociceptive pain Pain due to tissue damage; can be either somatic or visceral Opioids in specific conditions 6 RCT Randomised controlled trial Opioids and problem drug use 6 SmPC Summary of Product Characteristics Transdermal patches 7 Pain emanating from muscles, skeleton, skin; pain in the parts of the Somatic pain Practical aspects of prescribing 9 body other than the viscera. Visceral pain Pain relating to any of the large interior organs of the body

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Introduction and background The use of strong opioids in the Table ONE: Classification of opioids management of cancer pain and Approved name palliative care is widely accepted. The Formulations available use of opioids to treat moderate to (some proprietary names) severe acute pain is also widely Buprenorphine (Temgesic®, Transtec®, BuTrans®) Sublingual, transdermal accepted. The use of opioids to treat Diamorphine Oral, injection ® chronic non-cancer pain, however, Dipipanone (Diconal ) Oral 1-5 ® ® Transdermal, oral remains controversial. Areas of Fentanyl (Durogesic DTrans , Matrifen , 6-8 ® ® ® ® transmucosal, sublingual, uncertainty include: Effentora , Abstral , Actiq , Instanyl ) nasal spray  safety and efficacy of opioids in the ® ® long-term Strong Hydromorphone (Palladone , Palladone SR) Oral opioids Methadone Oral, injection  propensity for strong opioids to cause Morphine (Oramorph®, Sevredol®, MST Continus®, problems of tolerance, dependence ® ® Oral, rectal, injection MXL , Zomorph ) and addiction Oxycodone (OxyNorm®, OxyContin®) Oral type(s) of chronic conditions that  Pentazocine Oral, injection should be treated with strong opioids Oral, injection  patient selection * (Zydol®, Zamadol®) Oral, injection  clinical goals. Codeine Oral, injection Weak ® ® The treatment objectives in chronic Dihydrocodeine (DF118 Forte , DHC Continus ) Oral, injection opioids ® non-cancer pain are subtly, but Meptazinol (Meptid ) Oral, injection significantly, different and more Note: oral formulations can be immediate or modified release complex than the goals of opioid * Tramadol can be a weak or strong opioid, depending on dose therapy in the settings of terminal Use of pharmacological options should opioid-sensitive pain. Tramadol is conditions or acute pain. The objective be based on the ladder considered as either a weak opioid or a of the treatment of chronic pain of non- developed by the World Health strong opioid, depending on the cancer origin includes, when possible, Organisation (WHO). Treatment should administered dose.9 The term weak not only management of painful start at the bottom of the ladder and opioid should not encourage lack of symptoms but an emphasis on ascend in accordance with response to caution in prescribing. maintaining functionality and continued medication in terms of both efficacy and Opioid pharmacology participation in society. These side effects. objectives can be thwarted by the use The term “opioid” refers to all of opioids. compounds that bind to opioid WHO analgesic ladder for chronic receptors. The term “” can be Chronic pain can be treated with a nociceptive pain: used to describe those opioids derived variety of non-pharmacological and Step 1 = non-opioid + adjuvant from the opium poppy; these include pharmacological measures. Non- Step 2 = weak opioid + non-opioid + morphine and codeine. Opioids include pharmacological options include: adjuvant semi-synthetic , i.e. drugs that  physiotherapy, Step 3 = strong opioid + non-opioid are synthesised from naturally  heat or cold pack application, + adjuvant. occurring opiates (e.g. diamorphine  graduated exercise programmes, (Adjuvants include corticosteroids, from morphine; oxycodone from  transcutaneous electrical nerve and anticonvulsants) thebaine), as well as synthetic opioids stimulation (TENS), and such as methadone and fentanyl.  cognitive behavioural therapy. How are opioids classified? It is acknowledged that these Opioids are classified as either strong Opioid receptors are widely distributed interventions may be difficult to obtain or weak (see Table ONE). Strong in the body. When an opioid binds to in the primary care setting and this may opioids differ from weak opioids in opioid receptors, analgesia may be be the reason why, for many patients, having a much broader dose range and accompanied by any of a diverse array the only available option is drug a proportionately greater effect can be of side-effects related to the activation treatment. achieved by increasing the dose in of receptors involved in other functions. These may have an effect on peristalsis

COMPASS Therapeutic Notes on the Use of Strong Opioids in Non-cancer Pain January 2011 1 (leading to constipation), may cause Table TWO: Effects of stimulation of mu, kappa, and delta receptors itch, or have an effect in the CNS (leading to miosis, drowsiness, or Receptor type Effects of stimulation Analgesia (mainly at supraspinal sites), respiratory depression, respiratory depression). Activation of Mu other CNS pathways by opioids may miosis, reduced gastrointestinal motility Analgesia (mainly in the spinal cord), less intense miosis and also produce mood effects, either Kappa dysphoria or euphoria. See Table respiratory depression, dysphoria TWO. Delta Uncertain, probably analgesia

Although several types of opioid (e.g. naltrexone, naloxone); they can What is meant by “chronic pain”? receptors exist (e.g. mu, kappa and reverse the effects of mu opioid Chronic pain is defined by the delta), opioid drugs largely produce agonists. Those opioids with a low International Association for the Study their analgesic effects via activation of activity at opioid receptors are called of Pain as “pain that persists beyond partial opioid agonists (e.g. normal tissue healing time, which is the mu opioid receptors; thus, opioids 12 used for pain are often described as buprenorphine) – increases in dose of assumed to be three months”. A study “mu agonists”. Mu drugs that have the these agents will only increase effects conducted in a community in the ability to fully activate opioid receptors up to a ceiling point, after which dose greater London area to quantify the increases produce no additional prevalence of chronic pain found that are referred to as opioid agonists or full 10,11 mu agonists (e.g. morphine, oxycodone effects. 46.5% of the general population reported chronic pain; low back and methadone). Those opioids that How is pain classified? problems and arthritis were the leading occupy but do not activate receptors See Figure ONE. causes.13 are referred to as opioid antagonists

Figure ONE: Pain Classification

Strong opioids in common use: Morphine, diamorphine, oxycodone, fentanyl and tramadol

Table THREE gives approximate 14 equivalent doses of various opioids. Table THREE: The approximate potency of various opioids

Morphine Opioid Route Equivalent 24 hour dose The drug most often associated with Morphine Oral 30 milligrams potent analgesia within the general Codeine Oral 240 milligrams population is morphine. Morphine tends Hydromorphone Oral 6 milligrams to be the standard against which other Oxycodone Oral 10-15 milligrams are compared. Alternative Methadone Oral 30 milligrams opioids have not demonstrated Fentanyl Transdermal 12 micrograms/hour advantages that would make them Buprenorphine Transdermal 20-35 micrograms/hour preferable as first-line drugs for Tramadol Oral 120 milligrams moderate to severe pain. Morphine Note: This is only a guide. Since there is considerable interpatient variation in the dosage and response can vary widely response to these drugs it is essential to titrate the dose.15 in the adult population. Older people may require smaller doses due to receptor sensitivity and impaired renal Table FOUR: Common drug interactions with opioids function, whereas the very anxious individual in pain may require a larger- Opioid Interacts with: Effect 14 , than-expected dose. Sedation, Antagonism of GI effect dizziness, nausea and constipation can be problematic (discussed in detail All CNS depressants Enhanced depressant effect later). These are especially common in Anticonvulsants Increased opioid metabolism the frail or elderly, and when using Cimetidine Reduced opioid metabolism large doses. Euphoria, dysphoria and Methadone Phenytoin, Rifampicin Faster elimination of opioid Increased bioavailability of itching may also occur with morphine, Morphine , and important drug interactions are morphine shown in Table FOUR. Despite these Phenobarbital Accumulation of norpethidine Phenytoin Faster elimination of opioid adverse effects, morphine is a Pethidine CNS excitation, hyperpyrexia, remarkably safe and effective MAOIs analgesic. convulsions Cardiac glycosides Increased risk of digoxin toxicity SSRIs Increased CNS toxicity Tramadol Sympathomimetic pressor MAOIs response

COMPASS Therapeutic Notes on the Use of Strong Opioids in Non-cancer Pain January 2011 2  Prescribing Note: Morphine Figure TWO(a): Oxycodone and morphine - Number of items dispensed in 80,000 Northern Ireland For reasons of familiarity, availability and cost (rather than superior efficacy over 70,000 alternative opioids) morphine is the first- 60,000 choice strong opioid. 50,000

Diamorphine 40,000 Oxycodone Mor phine Essentially a prodrug, diamorphine is 30,000 activated by deacetylation in the ofNumber items 20,000 plasma to monoacetylmorphine and hence to morphine. Diamorphine is 10,000 very lipid soluble and rapidly crosses 0 4 7 01 0 0 09 0/ 8/ tissue membranes, with a much more 03/ 06/ 00 002/03 0 004/05 005/06 0 007/08 00 rapid onset than morphine. However, 2 2001/02 2 2 2 2 2 2 2 2009/10 the duration of action is also shorter, in Time (financial year) the region of two hours. This rapid onset and offset, especially when Figure TWO(b): Oxycodone and morphine - Spend in Northern Ireland administered by the intravenous route, £3,500,000 greatly increases its addiction potential. £3,000,000

Oxycodone £2,500,000 Oxycodone is licensed for the management of severe pain. It £2,000,000 Oxycodone undergoes first-pass metabolism (50%) Spend £1,500,000 Mor phine when taken orally. It is initiated at a dose of 5 milligrams 4-6 hourly.16 It has £1,000,000 similar side-effects to morphine but £500,000 possibly less sedation. Like morphine, it £0 is available as a modified-release (m/r) 01 02 03 04 05 06 07 08 09 10 ® 00/ 01/ 02/ 03/ 04/ 05/ 06/ 07/ 08/ 09/ 0 preparation (OxyContin ), delivering 20 20 20 20 20 20 20 20 20 2 analgesia for about 12 hours. Time (financial year)

In non-cancer pain, m/r oxycodone has been found to be similarly or slightly who concurrently take tricyclic less effective than morphine.17,18 antidepressants, as they have a similar Compared to twice daily m/r Prescribing Note: Fentanyl mechanism of action. For the same oxycodone, once daily m/r morphine The three immediate release products reason, concurrent use with MAOIs resulted in significantly better physical (Abstral® sublingual tablets, should be avoided. 19 ® function and quality of life. In one Effentora buccal tablets, and Tramadol is licensed for moderate to 20 Instanyl® nasal spray) are not study, adverse effects were seen in severe pain, but may not be as equivalent dose-for-dose. Each 88% of patients on m/r oxycodone. effective as strong opioids in severe formulation has a different absorption 25 The place in therapy of m/r oxycodone pain. Short term studies in chronic pattern so they are not interchangeable. 26 is second-line after morphine, in osteoarthritis (OA) or low back pain Individual patient dose titration must be ® patients in whom morphine is carried out if patients are switched found that Tramacet (which contains inappropriate or not tolerated.21 Use of between products. tramadol 37.5 milligrams and a sub- oxycodone has increased over the last therapeutic dose of paracetamol 325 few years and so has its cost to the Buprenorphine milligrams per tablet) was as effective Health Service. Oxycodone is As a partial mu agonist, buprenorphine as paracetamol 300 milligrams plus considerably more expensive than has a ceiling effect on its agonist codeine 30 milligrams (both up to 8 or morphine and spend on it is activity. This partial agonism would 10 tablets/capsules daily), with similar disproportionate to the number of items presumably yield a ceiling effect for levels of tolerability. analgesia as well, which would limit the dispensed. See Figures TWO(a) & (b). The most common side effects of clinical use of the drug in pain tramadol are nausea and dizziness, Fentanyl management, but there is some As fentanyl is 500 times more lipophilic both occurring in more than 10% of question about the extent of this ceiling 27 than morphine, it can be administered 24 patients. Constipation is also ® effect in practice. by the sublingual (Abstral ), buccal common, occurring in between 1% and 27 (Actiq®, Effentora®), nasal Buprenorphine undergoes high first- 10% of patients. Hallucinations, (Instanyl®) and transdermal pass liver metabolism if swallowed, but confusion and convulsions, as well as (Durogesic®, Fentalis®, Matrifen®, due to its high lipid solubility (200 times rare cases of drug dependence and Mezolar®, Osmanil®, Victanyl®) routes. that of morphine) it is readily absorbed withdrawal, have been reported with 28 The efficacy and safety of transdermal from the oral mucosa or through the tramadol at therapeutic doses. fentanyl in the treatment of chronic non- skin. Thus, it is very effective when Tramadol is considered to be no more ® cancer pain for up to 12 months has administered sublingually (Temgesic ) effective than other weak opioid been evaluated.22,23 In general, patients or as a transdermal preparation analgesics and its safety profile is ® ® 29 reported satisfaction with the treatment, (BuTrans , Transtec ). See later for problematic. Tramadol has been with improvement of quality of life more information on the use of opioid promoted as a drug to be used scores and pain.22,23 patches. between the WHO Step 2 analgesics for moderate pain (such as codeine) Tramadol Fentanyl now accounts for a third of the and the WHO Step 3 analgesics (strong Although tramadol has some opioid cost of all opioids in Northern Ireland. opioids such as morphine) for severe activity, the majority of its efficacy is Almost 90% of this cost is accounted pain. However, evidence from clinically through noradrenaline and for by prescribing of fentanyl patches useful trials (particularly in primary reuptake inhibition. Since it lowers although newer buccal and intranasal care, chronic pain, and cancer pain) is seizure threshold it is best avoided if preparations may change this picture in sparse.28 the future. there is a history of epilepsy. Tramadol should be used with caution in patients

COMPASS Therapeutic Notes on the Use of Strong Opioids in Non-cancer Pain January 2011 3 Less commonly used strong opioids: pethidine, methadone Pethidine Methadone management of pain is 5-10 milligrams Pethidine was the first totally synthetic Methadone is a synthetic opioid given 6-8 hourly, later adjusted to the opioid. It has approximately one-tenth developed about 50 years ago and has degree of pain relief obtained.16 During of the potency of morphine, and like been considered as an option for the prolonged use methadone should not other opioids undergoes extensive first- management of pain for a number of be given more frequently than every 12 pass metabolism (47-73%). years, especially chronic pain that is hours because of its long half-life.16 Convulsions may occur with repeated unresponsive to other analgesics. Its Although the half-life of methadone is dosing due to one of the metabolites, long and variable half-life due to usually estimated at 15-60 hours, in norpethidine, which is a proconvulsant. extensive tissue binding makes dose some reports the half-life is as high as In addition, it should not be titration and switching from other 120 hours.34 In a patient for whom the administered to patients taking MAOIs opioids a challenge. The use of methadone half-life is 60 hours, it would as the combination can cause methadone for the management of pain take almost 12 days on a stable dose of hypertension, hyperpyrexia, appears to be inconsistent among methadone to approach a steady state. convulsions and coma. It was favoured clinicians, with some palliative Methadone should therefore be started in the past as a drug that avoided medicine, oncology and pain at low doses and titrated slowly. smooth muscle spasm in conditions management teams using it frequently such as renal colic. It is not as popular while others rarely or never using it.31 now and is no longer considered a first- The MHRA issued a warning in 2006 line analgesic due to concerns over about the risk of QT prolongation with adverse reactions, drug interactions methadone, especially in patients on (see Table FOUR) and norpethidine high doses.32,33 The recommended neurotoxicity.30 usual dose of methadone for the Adverse effects of opioid therapy 80% of patients taking opioids will where the opioid works. The Scottish experience at least one adverse effect. Medicines Consortium (SMC) has not The common adverse effects are:35 Prescribing Note: Newer laxatives accepted Targinact® for use in  Constipation Relistor® (methylnaltrexone) injection Scotland. is licensed for the treatment of opioid-  Nausea and vomiting Nausea and vomiting induced constipation only in terminally ill  Somnolence or drowsiness The incidence of opioid-induced  Itching patients when response to other laxatives is inadequate.16 nausea and vomiting is estimated to be  Dizziness or vertigo 10-40% depending on the opioid ® Resolor () tablets are administered and the disease state Opioid side effects in patients with licensed for symptomatic treatment of chronic pain can impair quality of life, studied, although untreated pain itself chronic constipation in women in whom can induce nausea. Nausea and increase morbidity, and may cause a laxatives fail to provide adequate relief. vomiting are both rated as highly patient to use less than the prescribed 38 dose of opioid or to discontinue therapy based on its impact on life and the distressing by patients. Gradual dose completely. A systematic review found frequency with which it occurs.37 Thus titration may forestall the occurrence of that 22% of patients with chronic non- an effective regimen of laxatives should nausea. Nausea or vomiting tends to cancer pain discontinued opioid be initiated at commencement of opioid diminish over days or weeks of therapy because of side-effects.36 therapy. continued opioid exposure. The use of regular cyclizine or Tolerance to some side-effects usually How should opioid-induced during the first week of treatment occurs within the first few days of constipation be managed? minimises this distressing symptom.14 initiating treatment; (e.g. nausea and Approaches to preventing or treating sedation usually become less opioid-induced constipation include:14,37 Somnolence or drowsiness Sedation most frequently occurs at problematic after 1-2 weeks). However,  Use of an opioid-sparing regimen pruritis and constipation tend to persist (e.g. adding an NSAID or adjuvant initiation of opioid therapy or when a and some side effects such as immune analgesic). significant dose increase occurs. Symptoms frequently resolve after a and sexual dysfunction are more  Use of laxatives - regimens to 1 few days, in which case reassurance apparent after long-term therapy. manage constipation are generally and education (e.g. warning the patient Patients using intermittent dosing anecdotally based, but it is commonly to avoid and driving) should schedules may not become tolerant to accepted that both a stool softener 37 prove sufficient. Sedation for extended side-effects. and a stimulant are required. The periods may be caused by long-term effectiveness and safety of Prescribers should anticipate, identify comorbidities or concurrent such a regimen is unclear. Bulk- and treat common opioid-associated medications. adverse effects and patients should be forming laxatives (ispaghula, advised about side-effects and the methylcellulose, sterculia) and Itching likelihood of their occurrence before osmotic laxatives (lactulose, Pruritus occurs in about 1% of patients starting opioid therapy. macrogols) are also commonly after systemic administration of opioids, employed. but its incidence rises to 8% and 46% Constipation  Use of an opioid antagonist to when epidural or intrathecal routes are Constipation is one of the most directly reverse opioid effects. A new employed, respectively.37 Opioids common opioid-related adverse ® cause histamine release from mast 36 product, Targinact (oxycodone effects. Most patients develop some plus naloxone) provides sustained- cells to varying degrees, which may degree of constipation after opioid release oxycodone with naloxone, account for the sensation of itch; initiation or dose increases, and which has a direct opioid antagonist however, fentanyl has not been shown constipation does NOT tend to resolve effect on the bowel (avoiding to cause histamine release, yet it still with continued opioid treatment. constipation), but the vast majority of causes itching.39 Despite controversy Research in a small group of patients the naloxone is metabolised as it about the role of histamine, opioid- with chronic non-cancer pain suggests passes through the liver and thus induced pruritus is routinely treated that constipation is the most does not have a systemic antagonist with . bothersome of the opioid side effects, effect on the central nervous system,

COMPASS Therapeutic Notes on the Use of Strong Opioids in Non-cancer Pain January 2011 4  Sedation Endocrine effects  Prescribing Note: Long-term  Depressed respiration Influences on both the hypothalamic- opioid-use and driving  Visible cyanosis pituitary-adrenal axis and the  Myoclonic jerks hypothalamic-pituitary-gonadal axis Opioids are thought to worsen the have been demonstrated in patients performance of tasks such as driving.  Snoring  Agitation taking oral opioids. These effects are This may well be the case on starting probably dose-related and can lead to:  Confusion opioids, but when patients in chronic Amenorrhoea, reduced libido, and  Vivid dreams, nightmares or  pain use opioid medication for many infertility in women, and weeks, this impression has not been hallucinations  Erectile dysfunction and diminished confirmed. In a structural, evidence-  In more severe cases – hypotension, coma, convulsions. libido in men. based review, there was no evidence of Patients should be told about these impairment of psychomotor abilities Note: the dose of opioid causing toxicity varies between individuals and effects before starting opioids. immediately after being given doses of Endocrine function should be opioids, or any consistent evidence for depends on medical co-morbidity (particularly renal or hepatic monitored regularly if symptomatically a greater incidence in motor vehicle indicated and patients should be violations or accidents in opioid- impairment) and concomitant 40 medication therapy, including over-the- referred to an endocrinologist for dependent or -tolerant individuals. advice regarding the benefits of Rather than impairing psychomotor counter medications and illicit drug use. hormone replacement. tasks, it has been illustrated that test The rise in opioid prescriptions has Immunological effects scores significantly improved in been paralleled by substantial Opioids have an immunomodulating patients with chronic back pain during increases in deaths from opioid-related 44 effect. Opioids may differ in their the long-term use of oxycodone or overdose. Until recently, it was 41 propensity to cause transdermal fentanyl. Long-term unclear whether these parallel trends immunosuppression. The relevance of therapy with opioids does not inevitably were related, but a recent study has this knowledge to the clinical use of impair complex skills such as driving, provided the first empirical evidence to but the decision to permit driving must opioids is not known. link prescribed opioids to both fatal and be made in individual cases. non-fatal overdoses in patients with Opioid-induced hyperalgesia chronic non-cancer pain.45 Overdoses Opioid-induced hyperalgesia describes Respiratory depression were most common at the highest the paradoxical phenomenon whereby Respiratory depression is a much opioid doses (the annual overdose rate a patient receiving opioids for the feared complication of the use of was1.8% among patients receiving 100 treatment of pain may actually become opioids for acute pain, but it is only milligrams per day or more of morphine more sensitive to certain painful likely to be a potential problem in equivalents), but importantly in public stimuli.46 Clinically, opioid-induced persistent pain if there have been major health terms, most overdoses occurred hyperalgesia may be characterised by changes in dose, formulation or route in the larger groups of people receiving pain that has become more diffuse and of administration. Accidental overdose lower doses. Most of the overdoses (in less defined in quality and has a wider is likely to be the commonest cause of both high- and low-dose groups) were distribution than the pre-existing pain respiratory depression. Particular medically serious, and 12% were state. The management of opioid caution is necessary for patients taking fatal.45 induced hyperalgesia is opioid dose more than one class of sedative reduction or changing to an alternative medication and in those with pre- When are the features of opioid opioid preparation. existing disorders of respiratory control, withdrawal more likely to occur? 42 such as obstructive sleep apnoea. Opioid withdrawal occurs when the drug is stopped suddenly, the dose is Do the different opioids have tapered too rapidly or when an opioid different adverse effect profiles? antagonist is given. Signs of opioid There is little evidence that (in equi- 42 withdrawal include: analgesic doses) commonly used  Sweating opioids differ markedly in their side-  Mydriasis effects. However, because of inter-  Piloerection patient variability, a patient may  Yawning respond more favourably to one opioid  Abdominal than to another. If a patient fails to cramps/vomiting/diarrhoea achieve useful analgesia or develops Bone and muscle pain intolerable side-effects with their initial  opioid regimen, it may be worth trying  Increase in usual pain an alternative opioid.42  Restlessness  Anxiety What is “opioid rotation”?  Rhinorrhoea Opioid rotation exploits differences in  Lacrimation efficacy and side-effect profiles of  Tremor specific opioid molecules. Different Treatment of acute withdrawal includes opioids have different intrinsic efficacies administration of intravenous fluids, at opioid receptors. In addition, glucose, -2 adrenoceptor agonists differences in side-effect profiles may (e.g. , ), and be in part due to individual opioid antispasmodic drugs. metabolites. Despite the relatively common practice of opioid rotation, What are the risks of long-term there are no randomised trials that opioid therapy? validate its effectiveness.43 There are currently insufficient data to quantify the risks of long-term opioid What are the features of opioid therapy.42 Concerns relate to the toxicity? effects of opioids on the endocrine and 42 Features of opioid toxicity include: immune systems and the risk of  Pinpoint pupils inducing a hyperalgesic syndrome.

COMPASS Therapeutic Notes on the Use of Strong Opioids in Non-cancer Pain January 2011 5 Opioids in specific conditions Osteoarthritis (OA) A summary of the guidance given by Table SIX: Use of Opioids in Osteoarthritis various bodies is given in Table SIX. Body/Guideline Summary of recommendations The efficacy of open-label extended- release morphine in a 26 week trial in  Offer paracetamol for OA pain if non-drug core interventions are inadequate. OA patients has been evaluated.47  If paracetamol or topical NSAIDs are insufficient, then Reductions in pain intensity and one suggested option is addition of an opioid analgesic. improved sleep measures were The guideline makes no distinction between weak and observed. However, improvements 49 strong opioids. NICE were NOT observed in physical  States that the evidence for using opioids in the condition function. Constipation and nausea were is “poor”, with virtually no good studies using opioids in the most frequent adverse effects peripheral joint OA, and little evidence to suggest that reported in over 80% of the patients. dose escalation is effective. It also states that there are Controlled-release oxycodone therapy few data comparing different opioid formulations or routes has also been shown to be safe and of administration. effective for patients with chronic, Weak opioids “can be considered” for refractory pain from moderate to severe osteoarthritis- OA of the knee or hip, where non-drug and drug options related pain.48 Osteoarthritis Research have been ineffective, or are contraindicated. Stronger Society International50 opioids should only be used for severe pain in exceptional Neuropathic pain cases, in addition to non-drug treatments, and that surgical Pharmacological treatment of treatment should be considered in these circumstances. neuropathic pain usually involves Opioid analgesics (without specifying weak or strong antidepressants or anticonvulsants; European League Against opioid) are useful alternatives for those patients with OA of however, effective analgesia is Rheumatism51,52 the hip or knee in whom NSAIDs are contraindicated, achieved in less than half of patients.53 ineffective or poorly tolerated. The role of opioids in neuropathic pain Joint guidance from the has been under debate in the past, but Pain Society, Royal Hospital-based services should not start long-term opioid is nowadays more widely accepted.54-57 College of Anaesthetists, therapy without support from a multidisciplinary pain Unfortunately, there is great variability Royal College of General management service and liaison with the patient’s primary in the trials of opioids in neuropathic Practitioners and Royal care team. 42 pain, leading to conflicting and often College of Psychiatrists confusing results. Overall, higher opioid shows a potential benefit in improving neither morphine nor oxycodone were doses are often needed for treatment of neuropathic pain symptoms, possibly significantly better than naproxen for neuropathic pain than for nociceptive due to its specific pharmacological relieving pain or improving function.3 58 pain. Opioids have efficacy in profile.62 One study64 showed that sustained- neuropathic pain that is similar to that release morphine significantly improved In its recent clinical guideline for of the tricyclic antidepressants and 63 pain relief and quality of life for patients management of neuropathic pain, gabapentin. However, as opioids result who remained in the study for 56 NICE recommends oral tramadol only in more adverse effects, they are not weeks. However, use of concomitant as a third-line option and recommends considered to be first-line treatments for strong short-acting opioids for 59,60 that treatment with opioids other than neuropathic pain. A substance that “breakthrough” pain was required in tramadol should not be started without might be specifically interesting in this 50% of patients. type of pain is tramadol. It has shown assessment by a specialist pain service.63 The NICE clinical guideline on low back efficacy in a variety of neuropathic pain 65 61 pain advises that strong opioids settings, with an NNT of 3.8. Further Chronic back pain should only be considered for short- advantages are the low abuse Opioids seem to have limited, if any, 5 term use in people with severe low potential, non-controlled drug status, value in chronic low back pain. A back pain and that referral for specialist availability as generic preparations and Cochrane review of opioids in chronic assessment should be considered for a reduced rate and severity of low back pain found that tramadol was those people who may require constipation. Buprenorphine also more effective than placebo but that prolonged use of strong opioids.65

Opioids and problem drug use “The patient uses opioids to relieve pain and maintain a normal

relationship with the real world; the addict takes opioids to escape Table FIVE: Tolerance, dependence, pseudoaddiction and addiction14,67 from reality.”66 Tolerance What is meant by “problem” use? A reduction in response intensity and duration following the repeated administration of a Evaluation of problem drug use in drug; this includes the side-effects as well as the beneficial effects. Analgesic response relation to prescribed opioids for pain generally improves with an increase in dose. Although this is a normal pharmacological relief has been hampered by confusion response, the dose should not have to be increased on multiple occasions. regarding the terms tolerance, Physical dependence dependence and addiction. This is a normal physiological response. Receptors become dependent on the presence of Terminology for patients using opioids an exogenous agonist. The sudden withdrawal of an agonist or the use of a substance with medicinally has been clarified by a antagonistic properties will precipitate a withdrawal response. Physical dependence consensus statement from the symptoms abate when an opioid is tapered slowly. American Pain Society, the American Pseudoaddiction Academy of Pain Medicine and the If inadequate analgesia is provided, the patient seeks further analgesia. In this situation, American Society of Addiction Medicine despite the patient asking for increasing doses of analgesia (because of inadequate pain relief), they tend to use their medication as prescribed. (See Table FIVE).These definitions Addiction distinguish between expected sequelae True drug addiction is the overwhelming desire to continue to use the same or greater dose of opioid therapy, including physical of a substance with psychomimetic properties. The desire is over and above that for dependence and tolerance, and the analgesia and involves both psychological as well as physical factors.

COMPASS Therapeutic Notes on the Use of Strong Opioids in Non-cancer Pain January 2011 6 more biologically and behaviourally  Longer use of opioids complex syndrome of addiction. The Note: the presence of risk factors  Prescribing Note: term “pseudoaddiction” has been should not be a reason for denying a Opioid dose escalation coined to describe behaviours such as patient opioid therapy if opioids are the Need for increased dose of opioids is not drug hoarding, attempts to obtain extra appropriate management of the painful 42 supplies and requests for early condition. Identification of risk should always indicative of problem drug use. prescription or increased dose that help the prescriber determine the Dose escalation may result because of: might be mistaken as signs of addiction degree of monitoring and support  Increase in intensity of underlying pain but are an attempt to obtain better pain needed to prescribe opioids safely. condition (disease progression) relief. When pain is relieved, these Discussions should be clearly  Development of an additional painful behaviours cease.42 documented and communicated to condition  Opioid tolerance How big a problem is misuse of other members of the patient’s healthcare team. If the clinician has  Opioid induced hyperalgesia prescribed opioids? The estimated risk of addiction to concerns about how the patient is taking his/her medication, frequency of prescribed opioids is variably reported. 42 Most data are derived from studies of review should be increased. analgesic efficacy that are usually of It is preferable that a person on a too short a duration to identify problems strong opioid attend the same relating to aberrant drug use. Longer healthcare professional for follow-up 75 term data are available, but these and repeat prescriptions. A simple require caution in interpretation as protocol such as that shown in Table study populations are not consistent SEVEN can be valuable in providing with respect to diagnosis and previous good patient care while minimising history, and because reported short- and long-term problems. prevalence varies depending on the criteria used to define addiction. Rates of addiction in non-cancer pain patients Table SEVEN: Considerations for prescribing strong opioids are reported as occurring in 0-50% of 14 42,68-73 in severe, chronic pain patients

Is it possible to predict which  Perform an initial assessment, including motor function and activity levels. patients are likely to be at risk of  Explain the reasons for using strong opioids. addiction to prescribed opioids?  State clearly that pain will be modified but rarely completely controlled. A number of factors are thought to  Discuss side-effects and interactions. indicate a risk of addiction to prescribed  An opioid trial can be useful (see later). opioids. These include:42,74  If possible use the oral route of administration.  Use only one opioid at a time.  Current or past history of substance  Agents with toxic metabolites, e.g. pethidine, should be avoided. misuse, including alcohol  Analgesic/antiemetic combination products should be avoided.  Family member with history of  Regular dosing as opposed to “as-required” prescribing should be used. substance misuse  Long-acting opioids or sustained-release preparations are preferred.  Male gender  Changes in dosage should be made promptly to gain rapid control of pain.  Younger adults  Regular follow-ups should be arranged.  Poor social support  Ensure that documentation is clear and complete.  Co-morbid psychiatric disorders Transdermal opioids/ opioid patches

the skin into the subcutaneous fat from Fentanyl 3-day patches  Prescribing Note: where it is absorbed into the systemic Fentanyl patches give up to three days 76 Opioid patches circulation. These drugs are very of potent analgesia. Since the potent but plasma levels take some transdermal fentanyl preparations are Buprenorphine patches are time to become therapeutic (see later). available as a reservoir or matrix available as either 4-day or 7-day ® Likewise, when the patch is removed, a formulation, it is best to prescribe the patches. Transtec are 4-day patches. ® depot of the drug remains in patches by brand as bioavailability BuTrans are 7-day patches. subcutaneous fat continuing to have an may vary between products. Fentanyl patches are 3-day effect for a further 12-24 hours. When a If a patient is started on a transdermal patches. Various brands including new patch is applied it should be at a Durogesic DTrans®, Fentalis®, fentanyl patch, evaluation of the ® ® ® different site to the previous one. Matrifen , Mezolar , Osmanil , analgesic effect should not be made Tilofyl®, and Victanyl are available. It is important when using transdermal before the system has been worn for 24 opioid preparations to be aware of hours. This allows for the gradual Opioid patches should be reserved opioid load in terms of equivalent daily increase in fentanyl concentration. If for patients with swallowing morphine dose.42 Table EIGHT shows necessary, dose should be adjusted at difficulties. approximate equivalent potencies of 48-72 hour intervals in steps of 12-25 Heat therapy is often recommended commonly used transdermal opioids. micrograms/hour. Previous analgesic as a non-pharmacological option for therapy should be phased out gradually Effect of skin temperature on opioid treatment of chronic pain. However, from time of first patch application. patients should be counselled NOT to patches use items such as heating pads, Skin temperature affects peripheral When use of fentanyl patches is electric blankets and heat lamps on blood flow so it is important to be aware stopped and the patch is removed it the area where the patch is. that a sustained rise in ambient or body may take up to 25 hours for the plasma temperature can increase the drug fentanyl concentration to decrease by Skin irritation is reported to occur in uptake substantially – a rise in body 50% - replacement opioid therapy about 9% of patients using 35 temperature of 3°C will result in an should be initiated at a low dose and transdermal opioids. 14 increased absorption rate of 30%. increased gradually.

Fentanyl and buprenorphine patches release a lipid-soluble opioid through

COMPASS Therapeutic Notes on the Use of Strong Opioids in Non-cancer Pain January 2011 7

Table EIGHT: Transdermal opioids – approximate equivalence with oral morphine42 Prescribing Note: Fentanyl Oral morphine patches 10 15 30 45 60 90 120 180 270 360 (mg/24 hours) Prescriptions for fentanyl patches can Transdermal be written to show the strength in buprenorphine 5 10 20 35 52.5 70 terms of the release rate and it is (micrograms/hour) acceptable to write “fentanyl 25 Transdermal patches” to prescribe patches that fentanyl 12 25 50 75 100 release fentanyl 25 micrograms per (micrograms/hour) hour. The dosage should be Note: Published conversion ratios vary and these figures are a guide only. Morphine expressed in terms of the interval equivalences for transdermal opioid preparations have been approximated to allow between applying a patch and comparison with available preparations of oral morphine. replacing it with a new one, e.g. “one patch to be applied every 72 hours”.77 Table NINE: Approximate dose equivalents of buprenorphine patch and oral opioid analgesics

Buprenorphine 4-day or 7-day Buprenorphine Buprenorphine Buprenorphine patches 10mcg/hour 5mcg/hour patch 20mcg/hour patch If a patient is started on a transdermal patch buprenorphine patch, evaluation of the 50-100 100-150 Tramadol <50 milligrams/day analgesic effect should not be made milligrams/day milligrams/day before the system has been worn for 72 ~30-60 ~60-120 ~120-180 Codeine hours for the 7-day patch and 24 hours milligrams/day milligrams/day milligrams/day for the 4 day patch. This allows for the ~60-120 ~120-180 Dihydrocodeine ~60 milligrams/day gradual increase in buprenorphine milligrams/day milligrams/day concentration. Previous analgesic Note: these doses do not imply equi-analgesia; they should be used as a rough guide to therapy should be phased out gradually estimate a safe starting dose of buprenorphine. Patients must be treated on an individual 77 from time of first patch application. basis and carefully titrated to pain control.

Absorption varies depending on the  Do NOT use soaps, alcohol, oils, Cost considerations application site of the patch and the lotions or abrasive devices to clean See Table TEN. plasma concentration of buprenorphine the skin prior to application. The skin can be up to 26% higher when applied must be dry prior to application. to the upper back compared to the side  Apply the patch immediately after it is of the chest. The clinical relevance of removed from the sealed sachet. this is unknown.  The patch should be worn ® BuTrans patches are available in three continuously. CPD into action: Audit of patch strengths. Their daily dose  After removal of a patch, a new patch prescribing of opioid patches equivalents to codeine, dihydrocodeine should not be applied to the same site and tramadol are shown in Table NINE. for the subsequent 3-4 weeks. Suggestion – identify patients in your The BuTrans® SmPC gives some practice who are being prescribed Buprenorphine patches have become specific instructions regarding use of opioid patches. Do they have highly popular in the last 5 years with a the patch: swallowing difficulties? Are they taking steady continuing growth in prescribing Apply the patch to non-irritated, intact opioids orally concurrently? Consider  and costs. In 2010, £4million was spent skin of the upper arm, upper chest, the appropriateness of ongoing in Northern Ireland on these patches. upper back or the side of the chest, treatment with patches. Can this large growth in use be justified but not to any parts of the skin with in terms of evidence and cost- large scars. effectiveness? The main problem with  The site of application should be these patches is lack of good relatively hairless. If the site is not comparative information versus other hairless, the hair should be cut with active drugs. We don’t know if they are scissors, not shaven. as effective and we don’t know if they are better tolerated.

Table TEN: Cost* of strong opioid analgesics licensed for non-cancer pain77

Cost of 28 days Drug† Dose treatment* 5-20 mcg/hour, 7-day patch (BuTrans®) £17.60 to £57.16 Buprenorphine patch 35-70 mcg/hour, 4-day patch (Transtec®) £27.51 to £55.00 Buprenorphine sublingual 200-400 mcg every 6-8 hours £8.62 to £22.98 tablet Fentanyl patch 12-100 mcg/hour, 3-day patch (non-branded or Durogesic DTrans®) £35.52 to £162.90 Morphine modified release 12-hourly capsules (Zomorph®), 10-200mg, twelve hourly £3.47 to £51.30 oral preparations 24-hourly capsules (MXL®), 30-200mg daily £10.91 to £46.15 Immediate-release capsules (OxyNorm®) 5-100mg, 4-6 hourly £22.72 to £682.05 Oxycodone Modified-release tablets (OxyContin®) 10-200mg, every 12 hours £24.92 to £498.32 * Costs are based on prices quoted in BNF60, September 2010 † Other formulations of these drugs may be available, but are not licensed in non-cancer pain.

COMPASS Therapeutic Notes on the Use of Strong Opioids in Non-cancer Pain January 2011 8 Practical aspects of prescribing opioids for persistent non-cancer pain Which type of patients may benefit Choice of route of administration the withdrawal of the opioid and the use from opioids? Opioids may be administered orally or of an alternative treatment should be Proper management of opioids in well- transdermally. Injectable opioids should considered.14 Despite this, it is not selected patients with no history of not be used in the management of unreasonable to use an escalating substance addiction or abuse can lead patients with persistent non-cancer pain opioid regimen with an agreed plan and to long-term pain relief for some except in extraordinary circumstances goals over several weeks to establish patients with a very small (though not and then only after consultation with a efficacy.14 The continued need for an zero) risk of developing addiction, specialised multidisciplinary pain escalating dosage after the first few abuse, or other serious side effects. management service.42 weeks indicates that tolerance may be However, the evidence supporting occurring and that specialist support An important goal of analgesic therapy these conclusions is weak, and longer- should be sought. for chronic pain is to provide sustained term studies are needed to identify the analgesia; therefore, regular patients most likely to benefit from 73 administration is required to ensure the treatment. Prescribing Note: Opioid dose next dose of analgesic is given before

Which types of pain may benefit the effects of the previous dose have If patients do not achieve useful relief of from opioids? dissipated. Consequently, many pain symptoms at daily doses between Opioids are not effective in every patients benefit from an extended- 120 – 180 milligrams morphine- patient with pain. No criteria have been release analgesic that can be equivalent, referral to a specialist in pain identified that predict good response to administered once or twice a day.81 medicine is strongly recommended.42 opioids in any particular condition. Extended-release analgesics can Therefore each patient who is provide prolonged, more consistent Trial of opioid therapy considered for treatment with opioids plasma concentrations of drug A closely monitored trial of opioid needs to be assessed for both efficacy compared with short-acting agents and therapy is recommended before and safety. Pain of both nociceptive minimise fluctuations that could deciding whether a patient is prescribed and neuropathic origin may respond to contribute to end-of-dose breakthrough opioids for long term use.42 The patient opioid therapy.4,35,78 There are no pain. In addition, extended-release may need two or three upwards conditions under which opioid therapy analgesics may provide better night- adjustments of opioid dose (if tolerated) is contraindicated, but prescribers must time pain control with less need for before effectiveness can be be aware of the likely efficacy of a night-time dosing. evaluated.42 If after reasonable dose range of interventions for a given titration, useful pain relief is not condition and use this information to Key point: The use of achieved or intolerable side effects guide management. immediate-release opioids is NOT occur, the trial of opioid therapy should 42 encouraged in chronic non-cancer be considered unsuccessful. If opioid Key Point: In most situations, pain. Where possible, oral, modified- therapy is not to be continued, the dose for most patients and most pains, release opioids administered at of opioid should be stopped by gradual 42 opioids should not be considered as regular intervals should be used. decrements. the first-choice treatment.42 Long-acting opioid formulations How should a person be assessed Use of opioids for chronic non-cancer generally last 8 to 72 hours, making prior to prescribing an opioid? pain remains controversial. Data on the them appropriate for patients with A minority of patients with chronic non- long term effectiveness of opioids for persistent chronic non-cancer pain cancer pain have quite unrealistic that requires stable, around-the- 14 chronic non-cancer pain are sparse, 82 expectations. It is therefore essential with inconclusive or mixed results.79 clock dosing. to discuss not only the diagnosis of Although extensive clinical experience their problem and the therapeutic suggests that opioids can improve pain options but also realistic goals. Failing and function in some patients,4,35 a Prescribing Note: to do so can result in regular significant proportion experience no Oxycodone preparations attendances at the surgery in an attempt to gain a complete return to improvement or worsening of OxyNorm® are immediate-release symptoms,64 and opioid use is normality. oxycodone capsules. One capsule is associated with a variety of potentially taken every 4-6 hours. It is good practice when assessing the serious adverse outcomes, including ® OxyContin are modified-release patient in pain to elicit a mental health harms related to drug abuse and 36,80 oxycodone tablets. One tablet is taken history, including screening questions diversion. 42 every 12 hours. relating to:

Choice of drug  Current/past history of depression or The choice of drug depends on clinical Drug dose anxiety circumstances, local experience and Pain treatment with opioids should start  Current/past history of substance expertise.42 There are no high quality with a low dose that is titrated upwards misuse according to analgesic effect and side RCTs that compare different opioids in 42  Family history of substance misuse the management of persistent non- effects. The patient must be warned A history of depression or anxiety, and cancer pain. Clinical experience that it may take some days to substance misuse (by the patient or a determine whether the drug is going to suggests that pethidine is particularly 42 family member) may be risk factors for unsuitable for patients with persistent be effective. The doses of opioids problematic opioid use. This pain.42 Its high lipid solubility and rapid used for chronic non-cancer pain in well information is needed to determine the onset/offset may predispose patients to conducted controlled trials usually degree of monitoring and support equate to less than 180 milligrams of problem drug use. Its active metabolite 42 needed to prescribe opioids safely. norpethidine can lead to serious side morphine equivalent in 24 hours. The goals of therapy should be agreed effects. It does not produce less There are no high quality data before starting opioid treatment and smooth muscle spasm than equipotent published that inform prescribers of the 42 assessed at each review. These goals doses of other opioids and so confers safety and efficacy of higher doses. should be clearly documented. Adverse no advantage for patients with visceral A major concern with repeated dosing 42 effects should be documented at every pain. of any opioid is psychological assessment.

dependence. In chronic pain, it is important to achieve pain control within 14 a week or so. If this is not achieved,

COMPASS Therapeutic Notes on the Use of Strong Opioids in Non-cancer Pain January 2011 9 Long term opioid prescribing supply, pharmacists should Websites If the opioid trial (as outlined above) is ensure that there is a a success the patient may wish to genuine clinical need and  Action on Pain: www.action-on-pain.co.uk continue taking opioids. Treatment may that such prescribing does  British Pain Society: www.britishpainsociety.org 42 be continued until: not pose an unacceptable  Chronic Pain Policy Coalition: www.paincoalition.org.uk  The painful condition resolves risk to patient safety.  International Association for the Study of Pain: www.iasp-pain.org  The patient receives a definitive pain Generic prescribing Pain Concern: www.painconcern.org.uk relieving intervention (e.g. joint There is a general  Pain Support: www.painsupport.co.uk replacement) consensus that it is best  The Pain Relief Foundation:  The patient no longer derives benefit NOT to switch between  from opioid treatment www.painrelieffoundation.org.uk differing preparations of  The patient develops intolerable side- potent opioids, especially effects transdermal and sustained-release of intravenous buprenorphine and  Use of opioids becomes problematic. preparations, as bioavailability may fentanyl in humans and rats. Br.J.Anaesth. 2005; 94: 825-834. differ to a clinical extent. In Northern Is there evidence that opioids are 12. Classification of chronic pain. Ireland, the Health and Social Care useful in the long-term for chronic Descriptions of chronic pain non-cancer pain? Board has listed the following strong syndromes and definitions of pain opioids as UNSUITABLE for generic The efficacy of opioids for chronic non- 86 terms. Prepared by the International cancer pain has been demonstrated in prescribing: Association for the Study of Pain, ® short-term trials,35 but little is known  Buprenorphine patches (BuTrans , Subcommittee on Taxonomy. Pain ® about whether these agents continue to Transtec ) Suppl 1986; 3: S1-226. be effective over the longer duration of  Fentanyl patches (Durogesic 13. Elliott, A. M., Smith, B. H., Penny, K. ® ® ® treatment typical for chronic non-cancer DTrans , Fentalis , Matrifen , I., et al. The epidemiology of chronic ® ® ® pain. Concerns have also been raised Mezolar , Osmanil , Tilofyl , pain in the community. Lancet 1999; ® about adverse effects that may arise Victanyl ) 354: 1248-1252. 14. Campbell, W. 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COMPASS Therapeutic Notes on the Use of Strong Opioids in Non-cancer Pain January 2011 11 study. BMC.Health Serv.Res. 2006; noncancer pain. J.Pain 2009; 10: 6: 46. 113-130. 69. Michna, E., Jamison, R. N., Pham, L. 85. Passik, S. D., Kirsh, K. L., Whitcomb, D., et al. Urine toxicology screening L., et al. Monitoring outcomes during among chronic pain patients on opioid long-term opioid therapy for therapy: frequency and predictability noncancer pain: results with the Pain of abnormal findings. Clin.J.Pain Assessment and Documentation Tool. 2007; 23: 173-179. J.Opioid.Manag. 2005; 1: 257-266. 70. Manchikanti, L., Damron, K. S., 86. NI Health and Social Care Board. McManus, C. D., et al. Patterns of Items unsuitable for generic illicit drug use and opioid abuse in prescribing. patients with chronic pain at initial www.dhsspsni.gov.uk/generic- evaluation: a prospective, exception-list-regional-jan-10-final.pdf observational study. Pain Physician 2010; 2004; 7: 431-437. 71. Katz, N. P., Sherburne, S., Beach, M., © Queen’s Printer and Controller of et al. Behavioral monitoring and urine HMSO 2011

toxicology testing in patients receiving This material was prepared on behalf of long-term opioid therapy. the Department of Health, Social Anesth.Analg. 2003; 97: 1097-102, Services and Public Safety by: table. Lynn Keenan BSc(Hons) MSc MPS 72. Fishbain, D. A., Rosomoff, H. L. and Medicines Management Information Rosomoff, R. S. Drug abuse, Pharmacist dependence, and addiction in chronic COMPASS Unit pain patients. Clin.J.Pain 1992; 8: 77- Pharmaceutical Department 85. HSC Business Services Organisation 73. Noble, M., Treadwell, J. R., Tregear, 2 Franklin Street, Belfast S. J., et al. Long-term opioid BT2 8DQ. management for chronic noncancer pain. Cochrane.Database.Syst.Rev. You may re-use this material free of charge 2010; CD006605. in any format or medium for private 74. Edlund, M. J., Steffick, D., Hudson, T., research/study, or for circulation within an et al. Risk factors for clinically organisation, provided that the source is recognized opioid abuse and appropriately acknowledged. The material dependence among veterans using must be re-used accurately in time and opioids for chronic non-cancer pain. context, and must NOT be used for the Pain 2007; 129: 355-362. purpose of advertising or promoting a particular product or service for personal or 75. Simpson, K. H. Opioids for persistent corporate gain. non-cancer pain: recommendations for clinical practice. Br.J.Anaesth. Please note that every effort has been 2004; 92: 326-328. made to ensure that the content of the 76. Kornick, C. A., Santiago-Palma, J., COMPASS Therapeutic Notes is accurate Moryl, N., et al. Benefit-risk at the time of publication. Readers are assessment of transdermal fentanyl reminded that it is their responsibility to for the treatment of chronic pain. keep up-to-date with any changes in Drug Saf 2003; 26: 951-973. practice.

77. BMA/RPSGB. British National Any queries on re-use should be directed to Formulary. BNF60 2010; Lynn Keenan (e-mail 78. Kalso, E., Allan, L., Dellemijn, P. L., et [email protected], telephone 02890 al. Recommendations for using 535629) opioids in chronic non-cancer pain. Eur.J.Pain 2003; 7: 381-386. With thanks to the following for kindly reviewing this document: 79. Noble, M., Tregear, S. J., Treadwell, J. R., et al. Long-term opioid therapy • Professor GD Johnston, Consultant for chronic noncancer pain: a Physician. Belfast Health and Social Care systematic review and meta-analysis Trust. Professor of Therapeutics and of efficacy and safety. J.Pain Pharmacology. Queen’s University Belfast.

Symptom.Manage. 2008; 35: 214- • Dr Pamela Bell, Lead Clinician Chronic 228. Pain Services. 80. Hojsted, J. and Sjogren, P. Addiction Belfast Health and Social Care Trust. to opioids in chronic pain patients: a literature review. Eur.J.Pain 2007; 11: The editorial panel for this edition of COMPASS Therapeutic Notes: 490-518. 81. Nicholson, B. Benefits of extended- Ms Kathryn Turner (Medicines Management release opioid analgesic formulations Lead, HSCBSO). in the treatment of chronic pain. Pain Dr Bryan Burke (General Practitioner) Pract. 2009; 9: 71-81. 82. Argoff, C. E. and Silvershein, D. I. A Dr Grainne Crealey (Health Economist, comparison of long- and short-acting CRSC)

opioids for the treatment of chronic Miss Veranne Lynch (Medicines noncancer pain: tailoring therapy to Management Advisor, Belfast LCG) meet patient needs. Mayo Clin.Proc. Dr Ursula Mason (General Practitioner) 2009; 84: 602-612. 83. Trescot, A. M., Helm, S., Hansen, H., Ms Joanne McDermott (Medicines et al. Opioids in the management of Governance Pharmacist, Western Office) chronic non-cancer pain: an update of Mrs Stephanie Sloan (Community American Society of the Interventional Pharmacist) Pain Physicians' (ASIPP) Guidelines. Pain Physician 2008; 11: S5-S62. Dr Thérèse Rafferty (Medicines Management 84. Chou, R., Fanciullo, G. J., Fine, P. G., Information Analyst, HSCBSO).

et al. Clinical guidelines for the use of chronic opioid therapy in chronic

COMPASS Therapeutic Notes on the Use of Strong Opioids in Non-cancer Pain ● January 2011 12 COMPASS THERAPEUTIC NOTES ASSESSMENT Strong Opioids in Chronic Non-cancer pain

COMPASS Therapeutic Notes are circulated to GPs, nurses, pharmacists and others in Northern Ireland. Each issue is compiled following the review of approximately 250 papers, journal articles, guidelines and standards documents. They are written in question and answer format, with summary points and recommendations on each topic. They reflect local, national and international guidelines and standards on current best clinical practice. Each issue is reviewed and updated every three years. Each issue of the Therapeutic Notes is accompanied by a set of assessment questions. These can contribute 2- 3 hours towards your CPD/CME requirements. Submit your completed MCQs to the appropriate address (shown below) or complete online (see below). Assessment forms for each topic can be submitted in any order and at any time.

If you would like extra copies of Therapeutic Notes and MCQ forms for this and any other topic you can: Visit the COMPASS Web site: www.centralservicesagency.n-i.nhs.uk/display/compass or Email your requests to: [email protected] or Phone the COMPASS Team on: 028 9053 5661

You can now complete your COMPASS multiple choice assessment questions and print off your completion certificate online: www.medicinesni.com www.nicpld.org

Are you a Pharmacist? Community Hospital Other (please specify) GP? Enter your cipher number: Nurse? Enter your PIN number:

Title: Mr/Mrs/Miss/Ms/Dr

Surname: First name:

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GPs and Nurses: Complete the form overleaf and return to: COMPASS Unit Pharmaceutical Department HSC Business Services Organisation 2 Franklin Street Belfast BT2 8DQ

Pharmacists: Complete the form overleaf and return to: Northern Ireland Centre for Pharmacy Learning & Development FREEPOST NICPLD Belfast BT9 7BL COMPASS THERAPEUTIC NOTES ASSESSMENT Strong Opioids in Chronic Non-cancer pain

For copies of the Therapeutic Notes and assessment forms for this and any other topic please visit: www.centralservicesagency.n-i.nhs.uk/display/compass or www.medicinesni.com

Successful completion of these assessment questions equates with 2 hours Continuing Professional Development time. Circle your answer TRUE (T) or FALSE (F) for each question. When completed please post this form to the relevant address shown overleaf. Alternatively, you can submit your answers online: should submit their answers at: www.medicinesni.com should submit their answers at: www.nicpld.org

1 Morphine: a Morphine tends to be the standard against which other analgesics T F are compared. b Older people may require larger doses of morphine than younger T F people. c A daily oral dose of 30 milligrams of morphine is approximately T F equivalent to a daily oral dose of 240 milligrams of codeine. d Morphine is considered to be the first-line choice of strong opioid. T F

2 Fentanyl: a Fentanyl sublingual tablets, buccal tablets and nasal spray are T F directly interchangeable dose-for-dose. b Fentanyl patches provide 3-days of analgesia. T F c Fentanyl patches should be prescribed generically. T F d If a patient is started on a transdermal fentanyl patch, evaluation of the analgesic effect should not be made before the system has T F been worn for 24 hours.

3 Buprenorphine: a Buprenorphine is available in both 4-day and 7-day patches. T F b Buprenorphine patches should be applied to the upper arm, upper T F chest, upper back or side of the chest. c If the area is hairy, the skin should be shaved before applying the T F patch. d Buprenorphine patches can cause skin irritation. T F

4 Adverse effects of opioid therapy: Opioids are well tolerated and seldom discontinued due to adverse a T F effects. Nausea and sedation usually become less of a problem after 1-2 b T F weeks of treatment with a strong opioid. c Constipation does not tend to resolve with continued opioid T F treatment. d Itching occurs in about 1% of patients taking an opioid. T F

5 Prescribing strong opioids in chronic non-cancer pain: a In general, strong opioids are first-line. T F b Pethidine is considered to be particularly useful in chronic pain. T F c If an opioid is considered necessary, an oral, modified-release T F opioid administered at regular intervals should be used. d When stopping an opioid, the dose should be tapered slowly. T F