Guidance on Amitriptyline use with opiates


  • A 48 Year old patient died due to coadministration of Oxycodone and Amitriptyline (Nov 2019), possibly due to over-sedation. The coroner criticised the lack of guidance on prescribing Amitriptyline and Oxycodone fromNICE and BNF (1).

  • Amitriptyline found to be most common reason for antidepressant associated deaths. The highest morbidityamongst all classes of antidepressants was with Tricyclic Anti-Depressants (TCA). And Amitriptyline was thecausative agent in two third cases within TCA category (2).

  • Amitriptyline adds to Anticholinergic burden for elderly (3). It has been suggested by various inappropriate polypharmacy and deprescribing guidelines to consider stopping Amitriptyline where possible.

The STOPP START toolkit (4) explains deprescribing of Amitrityline.

In absence of current guidance on co-administration of Amitriptyline with Opiates, it is essential that we analyse the individual drug or drug class profiles of both Opiates and TCA and draw some guidance to practice patient safety.

Following are some facts that has guided the advice

on concomitant use of Amitriptyline and Opiates.

  • Half-life of Amitriptyline is 25 hours on average and is achieved as a steady state after approximately 3 days’daily dosing

  • Half-life of Amitriptyline is much longer in elderly due to poor hepatic metabolism.

  • A compromised renal function has no bearing on Amitriptyline’s biotransformation.

  • Amitriptyline is the parent drug of Nortriptyline, this means that in body Amitriptyline transforms intoNortriptyline.

  • Both Amitriptyline and Nortriptyline can increase Serotonin levels centrally. Hence co- administration with otherserotonergic drugs can lead to serotonin levels elevation and risk of Serotonin syndrome. Examples of other drugs that increases serotonin levels are Tramadol, Triptans, Dextromethorphan (an anti-tussive agent), opiates, Gabapentinoids, SSRI (such as Citalopram, sertraline), SNRI (such as Duloxetine, Venlafexine).

  • Nortriptyline also has a half-life of 26H and needs only once daily dosing for the purpose of Neuropathic pain relief.

  • Nortriptyline or Amitriptyline is not licensed to be used for Neuropathic pain relief (BNF).

  • Nortriptyline is considered slightly less sedating and less toxic than Amitriptyline, although cautions andcontraindications are same as Amitriptyline (5)

  • Both too high and too low plasma levels of Nortriptyline (an active metabolite of Amitriptyline) are associated with lack of efficacy. A daily dose of Amitriptyline not exceeding 75mg yields best results, thisalso reflects in advice from BNF. Again individual ability to metabolise varies therefor starting at lower dose andincreasing cautiously is recommended (6).

  • Maximum recommended dose of any opiate is equivalent to 120mg Morphine/day (7).

  • We can calculate the equivalent dose of any opiate using this link: 2010.pdf

  • Whilst calculating daily use of opiate one must take into account the top-up doses of immediate releaseopiates used for breakthrough pain.

  • When calculation cumulative risk of CNS toxicity, all drugs that may enhance sedation or risk of serotonin syndrome should be considered.

  • Previous fall(s), known over dose, frailty, advanced age should all be determinants of medicine optimisation.

The guidance:

  • The dose of Amitriptyline should not increase 75mg. This is a recommendation for headache. prevention and Neuropathic pain. As for higher maximum dose (in BNF) for depression please note that BNF also states that thisdrug class is not recommended treatment for Depression.

  • Nortriptyline may be used where excessive sedation is a cause of concern. Please DO NOT forget that cautions and contraindications of Nortriptyline are not different from Amitriptyline.

  • Calculate equivalent morphine dose for all opiates and ensure no prescribing above 120mg/day ofMorphine is being practised. Please bear in mind that Codeine and Dihydrocodeine also need to be addedto total daily opiate dose.

  • NICE recommended Neuropathic pain pathway that a combination of Amitriptyline and one of thegabapentinoids is acceptable where one agent is insufficient in providing sufficient pain relief (8). However frequent reviews should be practised for early identification of undesirable effects of the combination.

  • There is no rationale to use Gabapentin and Pregabalin together, regardless of additional Amitriptyline. Should you identify such prescribing, please optimise to one of the gabapentinoids.

  • Tramadol is not recommended to be prescribed for long-term treatment for neuropathic pain in Primary caresetting (9).

  • Carry out a High Risk Drug Monitoring review (a coded entry for EMIS). If you have a template in your system to document patient education, shared decision making , agreement of ongoing dose, please use it for better care communication among healthcare providers

Implying the guidance:

  • Search for all patients who are being prescribed Amitriptyline + Opiates/ Benzodiazepines/ Gabapentonoid overpast 6 months. Refine your patient list by further adding coded entries of overdose, respiratory failure, frail, overthe age of 65Y, fall, severe COPD.

  • Search should include all Prescription types; namely, Acute, Repeat, Repeat dispensed, Auto.

  • Identify patients who are being prescribed Amitriptyline over 75mg/day. (These are your red

group patients.)

  • Identify patients who are being prescribed Amitriptyline (any dose) with an opiate of dose Equivalent to more than120mg of Morphine/day. (These are your red group patients).

  • Identify patients who are being prescribed amitriptyline (any dose) with a regular hypnotic. (these are your ambergroup patients)

  • Identify patients who are being prescribed Amitriptyline (any dose) with a regular gabapentinoid. (Theseare your amber group patients)

  • Identify patients who are being prescribed Amitriptyline (any dose) and have one of the co- morbidity as explainedin search inclusion criteria (this is your amber group patients)

  • All red group patients need to be reviewed as a priority Face 2 Face to discuss dosage adjustment in lightof potential unsafe prescribing.

  • Add a “review requested” warning on the dose of Amber group patients and aim to get through the list over 6month time. Any patients not reviewed in 6 months despite the message,

should be moved to red group at the 6 monthly audit.

  • Repeat the audit in 6 months.


  1. of-guidance-on-co-prescribing-oxycodone-and-amitriptyline/20039700.article




  1. b%20Version.pdf



  1. reduction.pdf

  2. pharmacological-treatment-for-all-neuropathic-pain-except-trigeminal-neuralgia




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