COMPASS Therapeutic Notes on the use of Strong Opioids 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 opioid 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 Pethidine Oral, injection patient selection Tramadol* (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 analgesic 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 “opiate” 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 opiates, 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 antidepressants 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 analgesics 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 Domperidone, than-expected dose. Sedation, Antagonism of GI effect dizziness, nausea and constipation can metoclopramide 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 Clomipramine, amitriptyline 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 serotonin 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 (prucalopride