Tackle prescription drug dependency with improved clinician training, says reviewBMJ 2019; 366 doi: https://doi.org/10.1136/bmj.l5497 (Published 10 September 2019) Cite this as: BMJ 2019;366:l5497
All rapid responses
We concur with Mahase and can comment on dose. Opioids provide effective pain relief in acute injury and advanced disease but are often sedating and doses higher than necessary for effective analgesia may be used to sedate distressed patients. Higher than necessary doses of opioids are likely increase risk without added benefit, particularly a risk of dependency.
With all pharmacotherapy, it is prudent to ‘start low and go slow’. Adverse effects are multiple and generally dose-related. Dose-response will vary with pharmacokinetics,1 patient size and mental state. Intermittent use may be more rational and minimise habituation. Dosing, based on effective dose 50, ED50, may be a useful strategy for optimizing risk-benefit. ED50, the median population dose that reduces pain 50% of the maximal possible, Emax,2 was estimated from clinical pain studies and comparative pharmacodynamic evaluations in humans.3
The Table below summarises the ED50 and currently approved dose ranges of common opioids. Approved codeine doses can be seen to be well below ED50 and mainly benefit milder pain. Tramadol and Tapentadol are not available at doses below ED50 and are consequently often not tolerated. Dextropropoxyphene was approved at one dose, 5-fold ED50 and was ultimately withdrawn because of mortality, in particular related to respiratory depression. Oxycodone, morphine and hydromorphone are available at over 10-fold ED50, which may not be well tolerated and contribute to mortality. Psychotropics may be co-prescribed in pain management and some are also presented in Table 1, for comparison. It can be seen that SSRIs are also available at very high doses, in part likely related to competitive marketing.
As drug dose is increased above ED50, efficacy plateaus but multiple adverse effects continue to increase. Adverse effects also increase with time, which increase with the ‘area under the curve’. Multiple pharmacotherapy is common and adverse effects can increase from drug interactions. Comorbidities may increase sensitivity to opioids, for example neurological illness (pharmacodynamic) or with reduced excretion in impaired liver function (pharmacokinetic). Clinicians may be persuaded to use available higher doses (Table 1), sometimes unwittingly for off-label effects like anxiolysis and sedation. Smaller doses may prove sufficient and can reduce habituation and adverse effects.
On safety grounds and given the high reported mortality attributed to opioids, it is unclear as to why higher doses are approved. Least necessary doses should usually be employed, with prudent monitoring. Opioids may be best started around mean population ED50 and increased if greater efficacy is required and can be demonstrated, and reduced if adverse effects develop.
Table. Approved, maximum and ED50 doses of common CNS and CVS drugs
Drug Maximum Approved Mean population
reported oral ED50 dose (estimated)
(mg) (mg) (mg)
(as ratio of ED50)
citalopram 80 10-40 (3-14) 3
sertraline 200 50-100 (5-11) 9
fluoxetine 80 10-60 (3-20) 3
paroxetine 60 10-40 (2-8) 5
venlafaxine 400 37.5-225 (6-38) 6
chlorpromazine 2000 25-100 (0.2-0.7) 150
haloperidol 20 0.5-2.5 (0.5-2.5) 1
quetiapine 800 25-200 (0.2-1.3) 150
risperidone 16 0.5-2 (0.2-1.0) 2
olanzapine 60 2.5-20 (0.3-2.2) 9
methylphenidate 100 5-60 (0.5-6) 10
dexamphetamine 40 5-20 (0.5-2) 10
propranolol 320 10-160 (0.2-4) 40
metoprolol 400 50-100 (0.8-2.2) 60
hydrochlorothiazide100 12.5-50(1.2-5) 10
frusemide 500 20-40 (2-4) 10
captopril 300 12.5-50 (0.6-2.5) 20
perindopril 32 2-8 (0.5-2.0) 4
simvastatin 160 10-80 (0.6-5) 15
atorvastatin 80 10-80 (5-40) 2
rosuvastatin 40 5-40 (5-40) 1
warfarin 20 2-8 ¶ (0.3-1.3) 6 ¶¶
thyroxine 0.2 0.05-0.1 (0.7-1.3) 0.075 ¶¶¶
¶ 25th – 75th centile dose53 ¶¶ median population dose53 ¶¶¶ mean population dose54
1 Lotsch J. Pharmacokinetic-Pharmacodynamic modelling of opioids. Journal of Pain and Symptom Management. 2005; 29: S90-103.
2 Dimmitt S, Stampfer H, Martin JH. When less is more – efficacy with less toxicity at the ED50. Brit J Clin Pharmacol 2017; 83: 1365-8.
3 Faculty of Pain Medicine, ANZCA https://fpm.anzca.edu.au/documents/opioid-dose-equivalence.pdf
Competing interests: No competing interests
We read with interest Public Health England’s prescribed medicines review (1) and your news article covering the release of this (2). This landmark report details the extent of prescriptions of drugs with a risk of dependency in the UK. The ongoing opioid crisis in the USA has thrown into stark relief the susceptibility of doctors to over prescribing painkillers, and the consequences of this. An Oklahoma judge has recently decreed that the search for profit within the pharmaceutical industry is at least partly responsible for creating this epidemic (3). As Public Health practitioners, reviewing the current state of opioid prescribing and exploring avenues to reduce the risk of a similar crisis developing in England is of great importance to us.
The extent of opioid prescribing is lower in England than in the USA and, encouragingly, the annual number of prescriptions for opioid pain medicines has slightly decreased since 2016 after many years of rising. However, the proportion of these patients on long term (>= 12 months) opioid painkillers has continued to rise. This highlights the difficulty in stopping these medications once long term use has started.
Opioids are likely to be ineffective for the treatment of chronic (non-cancer) pain in all but a minority of cases. The Faculty of Pain Medicine has produced an Opioids Aware resource (4) which summarises the evidence around opioid use for chronic pain. It notes that “there is little evidence that they are helpful for long term pain” though “a small proportion of people may obtain good pain relief with opioids in the long term if the dose can be kept low and especially if their use is intermittent (however it is difficult to identify these people at the point of opioid initiation)”. Further, the evidence suggests that it is patients on long term opioids that are most at risk of dependence, eventual withdrawal and other adverse effects (1).
There has been much interest and research on the process of deprescribing (5), primarily focused on polypharmacy in the elderly. Deprescribing as a responsibility of the prescriber is a focus of the University of East Anglia’s toolkit for tackling chronic opioid use (6). Stopping opioids, especially in patients who have been taking them for a long time, is a difficult and time consuming process. Barriers to clinicians starting this process can include the expectation of patient resistance to change, the lack of effective alternatives and the difficulty of the process itself (7).
Though resources such as Opioids Aware (4) and the BMA’s chronic pain: supporting safer prescribing of analgesics (8) provide advice on broaching these topics and suggest tapering regimens, there is no NICE guidance specific to stopping prescription opioids and practice varies widely (9).
The report also shows significant variability in opioid prescribing at the CCG level. The percentage of the population receiving a prescription for an opioid in different CCGs varies between 5.7 and 20.6 percent (IQR 10.6 – 14.6 %). This variability is also present in the proportion receiving long term opioids, 32.5 – 60.7 % (IQR 45.3 – 53.6%). Importantly, the report found that the proportion of adults in receipt of a prescription with a retrospective duration of greater than 12 months increased in line with deprivation. Deprivation is associated with poorer overall health outcomes and tackling health inequalities is a key component of the NHS long term plan. Clinicians should be aware of the increased burden of chronic opioid prescriptions on the most deprived within society and reflect on their own practice as to whether they can change anything to reduce this. Clear clinical guidance on the use of opioids is needed to help standardise their use across regions and to reduce healthcare inequalities.
NICE recognise the need for updated guidance and are aiming to publish “Chronic pain: assessment and management” in 2020. They are also preparing guidance on “Safe prescribing and withdrawal management of prescribed drugs associated with dependence and withdrawal” with an expected publication date of 2021. We look forward to these guidelines and hope they will provide clinicians with the tools and evidence they need to minimise ineffective chronic opioid prescriptions, standardise practice across regions, and reduce healthcare inequalities.
The prevalence of patients currently prescribed long term opioid painkillers necessitates strategies and changes in practice aimed at stopping these medications for patients that are likely to find them ineffective. Clinician reflection, training and time are undeniably vital in combating the burgeoning opioid crisis, but clear guidance on the prescribing and deprescribing of these medications, along with alternative treatment pathways, are equally important, and needed urgently.
Kevin Joyce (1) & Padmanabhan Badrinath (2) email@example.com
1 Foundation Doctor in Public Health, West Suffolk NHS Foundation Trust, Hardwick Lane, Bury St. Edmunds, Suffolk IP33 2QZ, United Kingdom
2 Consultant in Public Health Medicine, Suffolk County Council, Endeavour House, IP1 2BX, Suffolk, United Kingdom.
The views expressed in this communication reflect the personal opinions of its authors and does not in any way represent the views of the authors’ employers.
1. Public Health England. Dependence and withdrawal associated with some prescribed medicines. An evidence review. [Internet]. 2019. Available from: https://www.gov.uk/government/publications/prescribed-medicines-review-r...
2. Mahase E. Tackle prescription drug dependency with improved clinician training, says review. BMJ. 2019 Sep 10;366:l5497.
3. Dyer O. Johnson and Johnson ordered to pay $572m in landmark opioid liability case. BMJ [Internet]. 2019 Aug 29 [cited 2019 Sep 13];l5319. Available from: http://www.bmj.com/lookup/doi/10.1136/bmj.l5319
4. Faculty of Pain Medicine. Opioids Aware: A resource for patients and healthcare professionals to support prescribing of opioid medicines for pain [Internet]. Available from: https://www.rcoa.ac.uk/faculty-of-pain-medicine/opioids-aware
5. Avery AJ, Bell BG. Rationalising medications through deprescribing. Vol. 364, BMJ (Online). BMJ Publishing Group; 2019.
6. University of East Anglia. Toolkit for tackling chronic opioid use in non-cancer Pain [Internet]. 2019. Available from: www.uea.ac.uk/pharmacy/research/chronic-opioid-use-in-non-cancer-pain/to...
7. Desveaux L, Saragosa M, Kithulegoda N, Ivers NM. Understanding the behavioural determinants of opioid prescribing among family physicians: A qualitative study. BMC Fam Pract. 2019 May 10;20(1).
8. British Medical Association. Chronic pain: supporting safer prescribing of analgesics [Internet]. 2017. Available from: https://www.bma.org.uk/collective-voice/policy-and-research/public-and-p...
9. Sandhu H, Underwood M, Furlan AD, Noyes J, Eldabe S. What interventions are effective to taper opioids in patients with chronic pain? BMJ. 2018;362.
Competing interests: No competing interests