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Opiates in palliative care

Strong opioids ,in particular morphine are the principal treatments for pain related to advanced and progressive disease ( NICE 2012 )


Pain is common in advanced and progressive disease and up to 2/3rd people with cancer will experience pain that needs strong opiates Opioids are available in different forms ( oral / transdermal / transmucosal / injectables ) and pharmacokinetics of the various opioids are very different and there are marked differences in bioavailability , metabolism and response among patients Opioids also come with different release characteristics
◘ Modified release ( MR ) used for background pain over a 24 hr period
◘ Immediate release ( IR ) preparations for as required breakthrough pain
oral IR morphine has an effect within 20-30 mins and peak in about 60 mins Individual selection for each patient and effective and safe titration -has a significant impact on pain control When deciding on initial dose of morphine – take into account 
○ previous / current analgesic use
○ renal function
○ co-morbidities
○ age
○ individual circumstances It is known that risk of harm increases substantially at doses above an oral morphine equivalent of 120 mg / day with no increased benefit and this is often used as a cutoff when primary care clinicians are advised to seek help from specialists


How do they work – Opioids provide analgesia by acting on receptors located on neuronal cell membranes Work by binding to receptors in the central and peripheral nervous system ( mainly delta , kappa and mu ) , these opiate receptors are located in the brain , spinal cord and the gut Morphine has higher affinity for Mu receptors than for other opioid receptors Action on mu receptors results in a complex cascade of intracellular signals resulting in dopamine release , blockade of pain signals and a resulting sensation and euphoria Opioids can be
○ based on action on the receptors agonists , antagonists or partial agonists
○ based on mode of synthesis – alkaloids , semi-synthetic and synthetic compounds Inhibition of neurotransmitter release ( presynaptic action ) is considered to be their major effect in the nervous system Via the above mentioned receptors they work on both CNS and PNS
◘ in CNS they have effect in many areas including the spinal cord
◘ in PNS they act on both the myenteric plexus and submucous plexus in the wall of the gut causing constipation In summary opioids work by inhibition of neurotransmission and binding of opioid receptors in the CNS and PNS Most opiates are excreted renally but for this to happen liver needs to produce derivatives with greater water solubility – ie impairment in one or both can significantly reduce clearance leading to accumulation


Long term use of opioids for non cancer pain has limited efficacy, risk of addiction in about 18 % , and studies have shown evidence of suppression of the hypothalamic / pituitary axis and immune suppression. Side effects include hypogonadotropic hypogonadism opioid induced androgen deficiency bone demineralization ( risk osteoporosis ) significant reduction in HDL-C


Communication – ask and address concerns regarding addiction , tolerance , side effects , fears that treatment implies the final stage of life provide written and verbal advice which covers aspects as how / when/why to use , efficacy , maintenance treatment and breakthrough pain, side effects & signs of toxicity , storage , follow up and who to contact during OOH particularly during initiation of Rx


Starting opiates – offer regular oral sustained release or oral immediate release morphine with rescue dose of oral immediate release morphine for breakthrough pain ( based on patient preference )
 assuming no renal/ hepatic impairment offer a typical daily starting dose of 20-30 mg oral morphine ( for e,g 10-15 mg of oral sustained release morphine BD ) +

5 mg oral immediate release morphine ( for e.g Oramorph ) for rescue doses during the titration phase – 
○ adjust to achieve a good balance between pain control and SEs and if after few dose adjustments a balance is not achieved seek specialist adv
 offer frequent reviews particularly in the titration phase
 in patients with moderate to severe renal or hepatic impairment seek specialist advice before prescribing strong opioids


1st line maintenance – NICE recommends using oral sustained release morphine as 1st line in patients with advanced and progressive disease who require strong opioids Review analgesic strategy and consider seeking specialist advice if pain is not adequately controlled and you have optimised 1st line maintenance treatment


Transdermal patches – transdermal preparations should not be used as 1st line maintenance treatment for patients in whom oral opioids are suitable consider for those where oral opioids are not suitable and analgesic requirements are stable -supported by specialist advice where needed


Subcutaneous delivery- consider S/C opioids for patients in whom oral opioids are not suitable, analgesic needs are unstable seek specialist advise when needed


Breakthrough pain – offer oral immediate release morphine for those who are on maintenance oral morphine treatment do not use fast acting fentanyl as 1st line rescue medication seek specialist advice if pain is not adequately controlled


Constipation – prescribe regular laxative treatment when initiating opioids and inform that constipation affects nearly all patients advice about adherence as treatment for constipation may take time and optimise management before considering switching strong opioids


Nausea – advice that nausea may occur when starting treatment but it is usually transient consider an anti-emetic if nausea persists before considering switching strong opioids


Drowsiness – warn that when starting strong opioids or at dose increase mild drowsiness or impaired concentration may occur but this if often transient driving – warn that this may affect their ability to drive drowsiness may also affect their ability to undertake manual tasks if the CNS side effects are persistent or moderate to severe
○ consider reducing the dose ( if pain is controlled ) OR
○ switching opioids if pain is not controlled if you have optimised treatment but the SEs remain uncontrolled seek specialist advice


Morphine – 1st line strong opiate for patients with normal kidney function ( WHO step ladder 3 – opiate of choice ) can be used in safely in liver failure but as the plasma clearance is reduced and elimination 1/2 life is prolonged use reduced doses and increased prn dosing intervals use lower dose , reduced frequency or alternative opioids if the patient has renal impairment , is elderly or cachexic


Diamorphine – highly soluble opioid can be used high-dose SC for breakthrough injections and via syringe driver ( can be given IM/ IV/ SC ) diamorphine is not a strong sedative potent opiate analgesic which acts more rapidly than morphine and acts primarily on the CNS and smooth muscles but has also a stimulant actions resulting in nausea , vomiting and miosis from a syringe driver it may take up to 4 hrs to build up to a steady state mostly excreted renally


Oxycodone – second line strong opiate used when morphine is not tolerated / adverse effects safer than morphine in patients with severe renal impairment or when the kidney function is deteriorating rapidly about twice as potent as morphine when used orally for breakthrough pain in patients on fentanyl / buprenorphine patch who cannot take morphine.


Buprenorphine – safe in renal impairment has both opioid -agonist and opioid antagonist properties analgesic effect is similar to morphine transdermal preparation only licensed for use in palliative care and constipation may be less severe patches take time to work and are not suitable for acute pain or when pain is changing rapidly


Fentanyl- strong synthetic opioid analgesia -about 100 to 150 times more potent than oral morphine constipation is less severe than other stronger opiates and may cause less sedation and nausea in some patients better tolerated in renal impairment transdermal patches ( other formulations as transmucosal and parenteral for specialist use ) initial analgesic use effect takes 12-24 hrs and lasts 12-18 hrs after the patch is removed oral morphine should be given for 1st 12 hrs and for prn use thereafter


Hydromorphone – opioid agonist with no antagonist activity produces less metabolites of morphine so theoretically has less side effects has mainly analgesic , anxiolytic , anti-tussive and sedative properties 1 mg hydromorphone is about equal to 7.5 mg oral morphine


Tapentadol – strong opioid with non-opioid properties (mu-agonistic opioid and additional noradrenaline reuptake inhibition properties ) exerts analgesic effect directly without a pharmacologically active metabolite SEs as with other strong opioids with additional risk of serotonin syndrome and seizures


Targinact- Oxycodone with naloxone option for those with opioid induced constipation expensive and laxatives are still required


Side effects – Constipation Nausea Drowsiness Dry mouth Hallucinations Nightmares Myoclinic jerks Pruritus


Tolerance – is complex and defined as reduced effect for the equivalent dose or the requirement of increased dose to attain the same effect
Tolerance is not seen for constipation or pupil constriction.
 Dependence – can be physiological or physical and differs from addiction. Physical dependence can lead to withdrawal symptoms and psychological dependence happens when the behavioural connections between analgesia and opioids is established.
CKS has defined the following key elements of opioid dependence
○ strong desire or sense of compulsion to take opioids
○ difficulty in controlling use
○ when opioid is reduced or stopped -it results in a physiological withdrawal state
○ evidence of tolerance
○ progressive neglect of alternative pleasures and interests
○ persistence with opioid use despite clear evidence of overtly harmful consequences
 Addiction – can be the result of many practices and behaviours. These can be for e.g drug-seeking behaviour ( multiple sources , legal , illegal ) compulsive use , abrupt withdrawal reactions , non compliance with suggested opioid changes and craving. It is seen more commonly when opioids are used outside the context of pain/ analgesia
 Withdrawal – can happen when opioids are stopped suddenly but can be seen also with tapered cessation. It can be acute , subacute and chronic. Widely known acute withdrawal symptoms include hot / cold flushes , nausea , vomiting , diarrhoea , sweating , lacrimation , insomnia , anxiety , generalized muscle pain , tachycardia , piloerection and dehydration. 
Can also be described as physical ( above symptoms ) and psychological when the patient fears a resurgence of previous pain
Withdrawal is not a sign of addiction or dependence
 Toxicitycontributing factors leading to toxicity can include rapid dose escalation , renal impairment , sepsis , electrolyte abnormalities , drug interactions○ excessive effect on the portion of brain regulating respiratory rate causing respiratory depression and death
○ symptoms can include persistent sedation , pinpoint pupils
( miosis ) vivid dreams , hallucinations , shadows at the edge of the visual field , delirium ,muscle twitching / myoclonus / jerking and abnormal skin sensitivity to touch
○ typical OD triad is pinpoint pupils , decreased level of consciousness and respiratory depressionNaloxone is the reversal agent used in opiate toxicity- see topic naloxone in opiate toxicityCeiling effect– dose escalation beyond a certain level does not confer any additional analgesic benefit
 Opioid Hyperalgesia -shares similar cellular mechanisms as with those of neuropathic pain and opioid tolerance and is described as a state of nociceptive sensitization caused by exposure to opioids. The patient may actually become more sensitive to certain painful stimuli & this type of pain experienced may not be different from the original underlying painful condition.


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