Opiate alkaloid isolated from the plant Papaver somnifera used in management of moderate to severe pain that may be acute or chronic
Morphine is a classic opioid analgesic which has an affinity for delta , kappa and mu -opioid receptors ( three major class )
Mu – Present in brainstem and thalamus. Role in supraspinal and spinal analgesia , sedation , inhibition of respiration, slowed GI transit , modulation of hormone and neurotransmitter release
Delta – Widely present in the brain , spinal cord and the digestive tract. Role in supraspinal and spinal analgesia , modulation of hormone and neurotransmitter release
Kappa – Present in the limbic system , diencephalon , brain stem and spinal cord . Role in supraspinal and spinal analgesia , sedation, psychomimetic effects , dependence
white crystalline solid used often in form of its sulfate salt an opiate agonist – binds and activates specific opiate receptors analgesic effect is primarily by binding to mu receptors in the CNS and PNS morphine and its metabolites act as agonists of the mu and kappa opioid receptors analgesic effect has both spinal and supraspinal components and simultaneous action on both- greatly amplifies analgesia leads to activation of descending inhibitory pathways of the CNS and PNS reduce the release of excitatory neurotransmitters inhibition of the primary afferent nociceptors to the dorsal horn sensory projection cells ( PNS ) ie blocks transmission of nociceptive signals the activation of the reward pathway is mediated by agonism of the delta -opioid receptors in the nucleus accumbens respiratory modification and addiction disorder -mediated by agonism of the mu-opioid receptors
Metabolism – absorbed in the alkaline environment of the upper intestine and rectum Significant first pass ( only about 40 % to 50 % of the amount absorbed actually reaches the nervous system ) that also means that oral doses are 6 times larger than parenteral doses to achieve the same effect Time to peak analgesia of 60-90 minutes and duration of 3-6 hrs very hydrophilic – this limits its capacity to penetrate tissues Reaches a steady state conc after 24-48 hrs Cleared primarily by glucuronidation in liver Main metabolite is 6-beta glucuronide ( M6G ) which is a potent opioid agonist that participates in the clinical effects of morphine ( responsible for about 80 % of the response observed by morphine administration ) Predominantly excreted in the urine Pubchem reports that peak analgesia occurs ○ within 60 mins of oral ingestion ( conventional preparation ) ○ 20- 60 mins after rectal administration ○ 50-90 min of S/C inj ○ 30-60 mins after IM inj ○ 20 mins after IV inj
Caution / contraindication – obstructive airway disease ( e,g asthma exacerbations ) respiratory depression previous hypersensitivity reactions patients who take MAOI’s – additive effect intestinal obstruction acute hepatic disease / obstructive biliary disease acute alcoholism head injury , ↑ ICP and coma convulsive disorders.
CNS – analgesia sedation mood and subjective effects ( calming effect , euphoria ) respiratory contre- dose dependent depression cough center is depressed by morphine temperature regulation – depressed ( hypothermia ) vasomotor centre depressed ( causing ↓ in BP )
chemoreceptor trigger zone ( nausea and vomiting ) Edinger Westphal nucleus ( miosis ) Vagal center ( bradycardia ) cortical areas and hippocampal cells -muscular rigidity and immobility at high doses
CVS – vasodilatation mild bradycardia ( ↓ vagal tone ) little effect with therapeutic doses in euvolemic patients
Gastrointestinal tract – Leads to constipation due to several actions as ↓ propulsion spasm of pyloric , ileocaecal and anal sphincters ↓ GI secretions.
Smooth muscle – spasm of sphincter of Oddi -can cause biliary colic urinary urgency and difficulty with micturition bronchi can cause bronchoconstriction
Respiratory – depression mediated via MOP receptors at the respiratory centre in the brainstem ( concomitant use of other CNS depressants for e.g BZPs may cause marked respiratory depression )
Smooth muscle – urticaria , itching , bronchospasm and hypotension
Renal failure – Morphine is metabolised into ○ morphine-3-glucoronide ( M3G ) 55 % ○ morpine-6-glucoronide ( M3G ) 10 % ○ hydromorphone , neuro-morphine and codeine these are all excretes renally along with about 10 % of parent compound reduced clearance of active metabolites can lead to accumulation Morphine 6 glucuronide this has the ability to cross the blood brain barrier and can cause prolonged CNS depression and analgesia using smaller doses and increasing dosing interval can help reduce drug toxicity Quitaiba et al recommend ♦ if GFR < 50 mL/min or less , reduce morphine dose by more than 50 % and avoid when possible ♦ if GFR < 30 – risk of toxicity is much higher and morphine avoidance becomes highly recommended.
Liver failure – 90 % of morphine is metabolised in the liver by the glucuronidation pathway half-life of oral and intravenous morphine is increased in patients with severe hepatic cirrhosis – cautious use is advocated there would be increased bioavailability in advanced chronic liver disease due to reduced first pass hepatic metabolism seek advice and use with caution in people with advanced chronic liver disease or cirrhosis if cirrhosis with concomitant renal failure- AVOID
Pain uncontrolled on maximum dose WHO step 2 opioid for mild to moderate pain ( eg Codeine 60 mg qds or Tramadol 100 mg qds Start Immediate release Morphine for eg Oramorph liquid or Sevredol tablets @ 5mg regularly 4 hrly Omit dose during night if sleeping Also prescribe sane dose 1-2 hrly as required for breakthrough pain
Start MR Morphine eg Zomorph MST Morphogesic @ 10 mg 12 hrly Also prescribe IR Morphine eg Oramorph liquid or Sevredol tablets @ 5mg 1-2 hrly as required for breakthrough pain.
Breakthrough pain is a transient exacerbation of pain occurring despite adequate background analgesia , this can be ○ spontaneous -here pain occurs without an obvious trigger e.g colic , neuropathic pain ○ incident pain ie due to an exacerbating factor e.g movement , swallowing , defecating , coughing , dressing changes , weight bearing ) Breakthrough pain is treated with an immediate release formulation of the same opioid where possible Breakthrough dose is 1/6th to 1/10th of the total daily opioid dose A common starting point is to prescribe 1/6th of the total 24 hrs dose to be given 2 hrly as required and adjusted according to benefit and tolerability If pain severe and recurring – advice not to repeat dose within 1 hr as delayed absorption may result in rapid accumulation. Seek advice about pain control
- Pubchem Morphine Morphine | C17H19NO3 – PubChem (nih.gov)
- Murphy PB, Bechmann S, Barrett MJ. Morphine. [Updated 2021 May 30]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK526115/
- Drugbank online Morphine: Uses, Interactions, Mechanism of Action | DrugBank Online
- EMC Morphine Morphine 10mg/5ml Oral Solution – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk)
- Greater Manchester Health and Social Care Partnership Palliative Care Pain & Symptom Control Guidelines *Palliative-Care-Pain-and-Symptom-Control-Guidelines.pdf (england.nhs.uk)
- Northern England Clinical Networks Palliative and End of Life Care Guidelines Symptom Control for cancer and non-cancer patients https://www.northerncanceralliance.nhs.uk/wp-content/uploads/2018/11/NECNXPALLIATIVEXCAREX2016-1.pdf
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- Dean M. Opioids in renal failure and dialysis patients. J Pain Symptom Manage. 2004 Nov;28(5):497-504. doi: 10.1016/j.jpainsymman.2004.02.021. PMID: 15504625.