Opioids for chronic non-cancer painBMJ 2013; 346 doi: https://doi.org/10.1136/bmj.f2937 (Published 29 May 2013) Cite this as: BMJ 2013;346:f2937
All rapid responses
Firstly I would like to thank Freynhagen et al., for an excellent and much needed up-to-date review of opioid therapy for a mainstream medical readership. Specialist pain and anaesthetic journals have covered this topic in some depth in recent years, but the general medical literature had few references for this topic. For this reason, this review is vital to raise awareness of the serious pitfalls of opioid therapy in the setting of general practice. Indeed, many developed countries have experienced something of an opioid epidemic over the last decade with the popularisation of opioid therapy for chronic non-cancer pain by many specialists.
Although numerous patients with chronic pain have benefited from long-term opioid therapy, I have also encountered a significant number of patients (in the UK and Australia) who have been commenced on opioid therapy without a structured regime as recommended by Freynhagen et al., Unfortunately in some cases, this has led to marked dose escalation to several hundred milligrams of morphine per day. For this reason, I would argue strongly against the recommendations that the authors give for managing the 36 year old carpenter with chronic low back pain. “…the doctor should advise that opioids are not likely to be helpful in his case… a multidisciplinary approach … will be more likely to restore function than simply prescribing of opioids, but may require referral to an appropriate pain service.”
It may seem pedantic and presumptuous, but I feel that many generalists may prefer specialists to give more direct and clear cut advice. The patient in question is a young man - only 36 - who presumably operates machinery for his job. Strong opioids such as morphine should be completely avoided in this scenario as they will cause significantly more harm than good, for all the reasons covered in the review and this should be made very clear to the patient.
Perhaps a case could be made for brief courses of tramadol for severe flare ups, but even that is questionable. Surely an exercise regime supervised by a physiotherapist should be the best way to manage the vast majority young people with back pain, rather than considering strong opioids? More complex patients must also be referred to a multidisciplinary pain clinic. If there are three certainties in life: death, taxes and back pain, then a liberal approach to the prescription of strong opioids for back pain will lead to an opioid epidemic.
Dr Stephen Humble
Competing interests: No competing interests
The article by Freynhagen et.al. (1) describes the lack of scientific evidence supporting prolonged opioid treatment of chronic non-cancer pain (CNCP). It compares unfavourably with other commonly prescribed classes of medications used to treat chronic conditions. A recent review noted there were about 1.8 million person years of observation in trials of medications for hypertension, three-quarters of a million person years for statin medications, and about 100,000 person-years in trials of NSAIDs, but only 1,500 person years in randomised trials of opioids for CNCP (2).
Nevertheless there has been an extraordinary increase of opioid prescribing over the last decade in some high income countries. In 2011, the most commonly prescribed drug in the United States was the opioid hydrocodone/paracetamol (3). Freynhagen et.al. state opioids are used for the indication of moderate to severe pain, however some reports show they are frequently prescribed for mild pain (4).
Escalating prescribing has paralleled overdose deaths as Freynhagen et.al. indicate. In the United States, between 1999 and 2010, there has been a four-fold increase in the number of poisoning deaths involving prescription opioids from 4,030 to 16,651 (5). Diversion was frequently (63.1%) associated with overdose deaths in one study from West Virginia (6).
Several of the many emerging toxicities from prolonged opioid treatment of CNCP are described by Freynhagen et.al., yet they maintain opioids may be chosen in those at risk of the complications of NSAIDs. However in one US survey of elderly arthritics, opioid users compared to NSAID users had higher rates of acute kidney injury, cardiac events and overall mortality. There was one additional death for every 27 prescribed opioids as against NSAIDs (7).
The authors claim "prescription of an abuse-deterrent formulation is a useful precaution" to minimise risks. These do seem to reduce injecting and intra-nasal use and this is reflected in their lower street value. It is important to make a distinction between ‘abuse-deterrence’ and ‘tamper-resistance’. New formulations of long-acting oxycodone resist crushing; and form a gel when moistened to deter parenteral use. These do not hinder those seeking a euphorigenic effect from taking supratherapeutic doses by mouth. Most abusers prefer the oral route (8). Such formulations, by reducing prescriber caution, may provide false confidence and lead to more liberal prescribing and increased costs.
Concerning the authors' suggested approach to prescribing; we wish to highlight the biopsychosocial nature of pain. Risk assessment prior to prescribing opioids is paramount, and must include taking a history covering social, family, drug and alcohol and psychiatric items. Nicotine addiction may be a further risk factor for drug dependence in CNCP (9). Doctors often find it easier to monitor what they can measure, so assessments such as the 3 question version of the Brief Pain Inventory (10) should be used both initially and regularly.
While use of opioids for acute pain is generally accepted, duration of therapy may be difficult to control. A US healthcare data study of those prescribed opioids continuously over 90 days and followed for up to half a decade found that about two-thirds remained on them (11). Some patients may never be able to taper or wean despite analgesic failure, toxicities or unfolding misuse (12) despite many faring better in terms of pain control and function by ceasing opioids altogether (13). Some patients and their prescriber will become trapped in decades of high dose opioid maintenance, with one study showing the top 5% of opioid users consuming 70% total opioid supply (14).
With such little evidence to support opioid prescribing for CNCP as safe or effective it is timely for Freynhagen et.al. to encourage us to carefully reconsider our analgesic practice: to minimise both individual and public health harms.
1. Freynhagen R, Geisslinger G, Schug SA. Opioids for chronic non-cancer pain. BMJ. 2013 2013-05-29 11:12:43;346.
2. Von Korff M, Rosenblatt R. Opioids for chronic pain: the status quo is not an option. 2012; (Wednesday, 18 July 2012 ): Available from: www.nwrpca.org/health-center-news/246-opioids-for-chronic-pain-the-statu....
3. IMS Institute for Healthcare Informatics. The use of medicines in the United States: Review of 2011. Parsippany, NJ: IMS Health Incorporated and its affiliates, 2012.
4. Toblin RL, Mack KA, Perveen G, Paulozzi LJ. A population-based survey of chronic pain and its treatment with prescription drugs. Pain. 2011;152(6):1249-55.
5. Chen L. Quickstats. Number of deaths from poisoning, drug poisoning and drug poisoning involving opioid analgesics - United States, 1999-2010 Atlanta, GA: National Center for Health Statistics 2013 March 29 Contract No.: 12.
6. Hall AJ, Logan JE, Toblin RL, Kaplan JA, Kraner JC, Bixler D, et al. Patterns of Abuse Among Unintentional Pharmaceutical Overdose Fatalities. JAMA. 2008 December 10, 2008;300(22):2613-20.
7. Solomon DH, Rassen JA, Glynn RJ, Lee J, Levin R, Schneeweiss S. The Comparative Safety of Analgesics in Older Adults With Arthritis. Archives of Internal Medicine. 2010 December 13/27, 2010;170(22):1968–78.
8. Kirsh K, Peppin J, Coleman J. Characterization of prescription opioid abuse in the United States: focus on route of administration. J Pain Palliat Care Pharmacother. 2012 Dec;26 (4 ):348-61.
9. Fishbain DA, Cole B, Lewis JE, Gao J. Is Smoking Associated with Alcohol-Drug Dependence in Patients with Pain and Chronic Pain Patients? An Evidence-Based Structured Review. Pain Medicine. 2012;13(9):1212-26.
10. Krebs EE, Lorenz KA, Bair MJ, Damush TM, Wu J, Sutherland JM, et al. Development and Initial Validation of the PEG, a Three-item Scale Assessing Pain Intensity and Interference. Journal of General Internal Medicine. 2009;24(6):733-8.
11. Martin B, Fan M-Y, Edlund M, DeVries A, Braden J, Sullivan M. Long-Term Chronic Opioid Therapy Discontinuation Rates from the TROUP Study. Journal of General Internal Medicine. 2011;26(12):1450-7.
12. Ballantyne J, Sullivan MD, Kolodny A. Opioid dependence vs addiction: A distinction without a difference? Archives of Internal Medicine. 2012;172(17):1342-3.
13. Murphy JL, Clark ME, Banou E. Opioid Cessation and Multidimensional Outcomes After Interdisciplinary Chronic Pain Treatment. The Clinical Journal of Pain. 2012;Publish Ahead of Print, Jun 28:10.1097/AJP.0b013e3182579935.
14. Edlund MJ, Martin BC, Fan M-Y, Braden JB, Devries A, Sullivan MD. An Analysis of Heavy Utilizers of Opioids for Chronic Noncancer Pain in the TROUP Study. Journal of Pain and Symptom Management. 2010;40(2):279-89.
Competing interests: No competing interests
Opioids for chronic non-cancer pain – Chemotherapy – Clinical Guidelines: Where does Ultimate Responsibility Lie?
With the current pages of the BMJ showing misgivings about (a) Opioid use for chronic non-cancer pain , (b) Chemotherapy , (c) Clinical Guidance and Guidelines  – most diligent doctors are forced to ask “Who takes ultimate responsibility for the satisfactory care of our patients?”
DOES “MODERN” MEAN “BETTER” IN HEALTH CARE DELIVERY?
Dr R Freynhagen and colleagues present 19 excellent recommendations for doctors “prescribing opioids” – recommendations which challenge modern trends and the “aggressive marketing (that) have driven a dramatic increase in (opioid) use with more adverse events including deaths from over-dosage” . Indeed, the UK National Confidential Enquiry into Patient Outcome and Death (NCEPOD) revealed that “Nine out of the 19 patients with sickle cell disease who had pain on admission and who then died had been given excessive doses of opoids” [4 5]. I voiced my displeasure at this revelation , having pointed out previously that directing the largest Sickle Cell Clinic in the world I had never used morphine or diamorphine for a single one of the hundreds of patients I had supervised in Ghana with sickle cell crisis [7-10], nor had Graham Serjeant, the English man who in Jamaica directed the second largest clinic and who also had treated hundreds of sickle cell disease patients in pain [11-13]. Clinicians in the UK and USA are also prescribing oral morphine, in my opinion inappropriately, for the chronic arthritic pain from avascular necrosis of the femoral head in these patients. Has “aggressive marketing”  anything to do with this? 
IMPERSONAL GUIDELINES VERSUS CONSULTANT RESPONSIBILITY
Dr Des Spence, in his usual forthright manner, bemoans the received wisdom that makes doctors just follow what Guidelines recommend – often leading to individual clinical judgement being abandoned in favour of prescribed Guidelines that are inimical to the patient’s well being. “History will judge our era as one of iatrogenic harm” concludes Des Spence . Consultants no longer appear to take responsibility for what goes wrong – preferring rather to defer to Guidelines, sometimes very “nice” ones . The recent question mark over Guidelines, namely that “guidelines continue to be followed despite concerns about bias”  makes it all the more necessary that Consultants under whom patients are admitted take responsibility when things go wrong.
BRITISH MINISTERS OF HEALTH ECHO SIMILAR SENTIMENTS
Please do not dismiss my comments as the frustrated cogitations of a mid-20th Century British-trained African physician longing for the “good old days” when Consultants did what they knew was right and did not go round saying “The Guide Lines say this is what we should be doing”. British Ministers of Health would agree with me, because less than a fortnight ago, on Thursday 13th June, when interviewed for ‘The World at One’ News Bulletin Health Secretary Mr Jeremy Hunt said: “Where poor care exists we should not tolerate it. This is about Responsibility and Accountability”. One previous Health Secretary, Mr Stephen Dorrell, on the same programme also said that “Doctors should be accountable for the service delivered”. Neither Health Minister looked to blame Guide Lines and Guidance. Expertise does not at all appear to be the problem. Last Tuesday 19th June 2013, WORLD SICKLE CELL DAY, Tunu Louise Roberts, that accomplished former BBC interviewer, broadcast a 25-minute interview  for listeners in Africa and world wide, during which she asked me about the success of our work with sickle cell disease patients in Ghana whom we aimed at helping to become “Achievers in various professions”. My answer was simple: “Dedication, not so much expertise, is what is required to produce achievement in sickle cell disease patients whom I call ACHEACHE (ACHE gene from father and ACHE gene from mother). When we admitted patients at 5 pm very ill I, the consultant physician, would visit the ward at 11 pm to see if the nurses were doing what we ordered”. Graham Serjeant also did the same, enabling a sickle cell anaemia patient from Jamaica to go to Oxford University, just as we helped another ACHEACHE lady, now in her seventh decade of life, from Ghana to become Professor of Law after postgraduate work also in Oxford University. Serjeant and I, with our superb mid 20th Century British undergraduate and post-graduate training need no NICE Guide Lines to manage our patients [17 18]. We never gave regular blood transfusions to our sickle cell disease patients as if they had beta-Thalassaemia major, we never treated them with morphine or diamorphine for pain, and we never prescribed 500 mg Hydroxyurea daily as the Guide Lines stated. When the iatrogenic renal failures get out of hand Des Spence’s words will be remembered.
Competing Interest: Three of my parents’ 11 children had sickle cell disease (www.konotey-ahulu.com/images.generation.jpg) hence my critical scrutiny at how patients are managed or mismanaged.
1 Freynhagen Rainer, Geisslinger Gerd, Schug Stephan A. Opioids for chronic non-cancer pain. BMJ 2013; 346: 1237 doi:10.1136/bmj.12937 June 22, pages 38-41.
2 Spence Des. Saying ‘No’ to chemotherapy. BMJ 2013.346.doi. http://dx.doi.org/10.1136/bmj.14023 June 21 2013
3 Lenzer Jeanne. Why we can’t trust Clinical Guidelines. BMJ 2013; 346: f3830. June 22 2013, pages 20-22.
4 NCEPOD (National Confidential Enquiry into Patient Outcome and Death}. Sickle: A Sickle Crisis? (2008) [Sebastian Lucas (Clinical Co-ordinator), David Mason (Clinical Co-ordinator), M Mason (Chief Executive), D Weyman (Research), Tom Treasurer (Chairman) firstname.lastname@example.org
5 Mayor Susan. Enquiry shows poor care for patients with sickle cell disease. BMJ 2008, 336: 1152.
6 Konotey-Ahulu FID. Poor care for sickle cell disease patients: This wake-up call is overdue. BMJ Rapid Response 29 May 2008. http://www.bmj.com/rapid-response/2011/11/02/poor-care-sickle-cell-disea...
7 Konotey-Ahulu FID. Morphine in sickle cell disease. BMJ 1991; 302: 1604
8 Konotey-Ahulu FID. Opiates for sickle cell crisis? “The question that puzzles me is: Why do West African and West Indian patients with sickle cell disease who did without morphine in their countries have to be given morphine pumps during sickle cell crises when they come to the UK?” Lancet 1998; 351: 1438.
9 Konotey-Ahulu FID. Opiates for sickle cell crisis. “When I say routine opiates for sickle cell crisis are not the way to bring out these patients’ best potential in the long term I am glad to hear white physicians say the same … White physicians who, at the risk of being misunderstood by (named British Consultant Haematologist), voice their displeasure at what they see happening on their wards deserve commendation, not condemnation” Lancet 1998; 352: 651-652.
10 Konotey-Ahulu FID. The Sickle Cell Disease Patient: Natural History from a Clinico-epidemiological study of the first 1550 patients of Korle Bu Hospital Sickle Cell Clinic. London: Macmillan 1991; Watford: Tetteh-A’Domeno Company, 1996.
11 Serjeant Graham. Sickle Cell Disease. Oxford: Oxford University Press, 1985, page 204 > “In Jamaican experience morphia or its derivatives are rarely used or necessary”.
12 Serjeant Graham. Sickle Cell Disease. Oxford: Oxford University Press, 1992.
13 Serjeant Graham R. Sickle Cell Disease. Lancet 1997; 350: 725-30.
14 Konotey-Ahulu FID. The politics (and economics) of pain relief in the West and World h
BMJ Rapid Response 24 June 2010. http://www.bmj.com/rapid-response/2011/11/02/politics-and-economics-pain...
15 Konotey-Ahulu FID. Management of acute painful sickle cell episode in hospital: NICE Guidance is frightening! BMJ Rapid Response Sept. 7 2012. http://www.bmj.com/content/344/bmj.e4063/rr/599158
16 WORLD SICKLE CELL DAY Broadcast on The Sickle Cell Disease Patient 19 June 2013 Tunu Louise Roberts interviews F I D Kootey-Ahulu [Can be heard again on Home Page of www.sicklecell.md or on YouTube]
17 Serjeant Graham. The case for dedicated sickle cell centres. BMJ 2007; 334: 477 (3 March).
18 Konotey-Ahulu FID. Dedicated sickle cell centres. BMJ Rapid Response March 20 2007 http://www.bmj.com/rapid-response/2011/11/01/dedicated-sickle-cell-teams
Competing interests: Three of my parents' 11 children had sickle cell disease (www.konotey-ahulu.com/images.generation.jpg) hence my critical scrutiny at how patients are managed or mismanaged.
A very helpful overview about the use of opioids for non-cancer pain 1. The authors rightly point out, how right at the beginning of the treatment, a realistic and pragmatic goal should be set-up.
Anecdotally, I have seen patients who scored low on the opioid risk tool being dependent on prescribed opioids and who were using the medications for reasons other than pain.
Opioid analgesia is used for acute and chronic pain relief and some of them are listed as essential medicines by the world health organistaion (WHO) 2. The sporadic and regular use of opioid analgesia for chronic and non cancer pain has led to dependence on these medications. Evidence from a health centre in Pennsylvania suggested that 21.7% of patients met the criteria for moderate opioid-use disorder while 13.2% of patients have severe opioid-use disorder 3. In 2006 a worldwide comparison found the United Kingdom was listed as a moderate consumer of opioid based analgesia and it was indicated that the consumption of Morphine equivalents doses were 99.14 mgs/ capita 4. In the United States, the number of deaths which are associated with opioid analgesic drug has been steadily increasing since 1999 and in 2007 they outnumber the deaths associated with heroin and cocaine 5.
The Leeds Addiction Unit set up the Leeds Polypharmacy Clinic in April 2012, which deals with patients dependent on prescribed and over-the-counter medications as well. We are currently in the process of evaluating the service, but analysing a sub-sample of patients reported 70% being dependent on opioid analgesia out of which approximately 43% were using codeine based medications. We also have physical health concerns, particularly when codeine is available over-the-counter in combination with Paracetamol (Co-Codamol), which can be hepatotoxic and Ibuprofen (Neurofen Plus), which can cause gastric bleeding. There has been increasing interest in this issue by politicians, commissioners and clinicians.
1. Freynhagen R, Geisslinger G, Schug AS. Opioids for chronic non- cancer pain. BMJ 2013;346:f2937
2. World Health Organization. WHO Model List of Essential Medicines, 15th List. Geneva: World Health Organization; 2007. Available at: http://www.who.int/medicines/publications/ 08 ENGLISH index FINAL EML15.pdf.
3. Medically induced opioid addictions reaching alarming levels. CMAJ, February 21, 2012, 184 (3): 285- 86
4. Seya MJ, Gelders SFAM, Achara UA, Milani B, Scholten WK, J Pain and Palliative Care Pharmacotherapy, 2011; 25: 6-18
5. Holmes D. Prescription drug addiction: the treatment challenge. The Lancet; Vol 379( Iss 9810), 17-18.
Competing interests: No competing interests
This article highlights an important public health issue, in the light of increasing prescriptions and reports of doubtful efficacy, especially in the long-term. One of the problems, however, facing researchers in this field, is the lack of a gold-standard definition of CNCP, and a poor handle on prevalence studies internationally. Reid et al. (2011) reviewed the international literature and examined the prevalence of CNCP, citing estimates sourced from questionnaire-based surveys. They defined CNCP as pain lasting at least three months, including musculoskeletal pain, neuropathic pain, fibromyalgia, osteoarthritis and rheumatoid arthritis, but excluding headache, migraine, angina pectoris, cancer pain, and pain associated with specific disease conditions (eg multiple sclerosis). I am presently researching the prevalence of CNCP in the UK prison estate, utilising Reid et al.’s definition (but also excluding pain of visceral origin), and taking as my intensity standard, pain that requires consumption of analgesic medication on a continuous daily basis.
The therapeutic implications of the CNCP epidemic are significant. However, before moving to more elaborate studies (urgently required), baseline prevalence studies such as mine are necessary to frame this problem epidemiologically. I would be very interested to hear from any other workers in the field, especially in UK Primary Care, who might be interested in collaborative / comparative studies, to take this further.
Competing interests: No competing interests
The authors usefully reference the hypogonadotropic hypogonadism (HH) commonly induced by long-acting opioid analgesics, of which the most serious potential long-term consequence is osteoporosis. However, whereas immune suppression is very much in the small print of HH, sexual dysfunction, fatigue and infertility are very much to the fore.
Indeed, testosterone replacement can exacerbate oligospermia through its additional negative-feedback constraint on pituitary LH and FSH secretion (1). If fertility is desired, then gonadotropin therapy rather than testosterone will be required, though where NHS funding for gonadotropins in men is locally unavailable (2), off-label use of oral Clomiphene could be an effective alternative (1,3).
Finally, alternative causes for HH (eg. prolactinoma) should always be considered in any opiate-treated man presenting with adult-onset HH.
1. Hill S, Arutchelvam V, Quinton R. Enclomiphene, an estrogen receptor antagonist for the treatment of testosterone deficiency in men. IDrugs. 2009 Feb;12(2):109-19.
2. Smith N & Quinton R. Patient Journey: Kallmann syndrome. BMJ. 2012 Dec 3;345:e6971. doi: 10.1136/bmj.e6971
3. Ioannidou-Kadis S,, Wright PJ, Neely RD, Quinton R. Complete reversal of adult-onset isolated hypogonadotropic hypogonadism with clomiphene citrate. Fertil Steril. 2006 Nov;86(5):1513.e5-9.
4. Merza Z, Edwards N, Walters SJ, Newell-Price J, Ross RJ. Patients with chronic pain and abnormal pituitary function require investigation.
Competing interests: No competing interests
We read the therapeutics article by Freynhagen et al. concerning the treatment of non-cancer pain with opioids with interest. (1) However, we were surprised to see only a cursory discussion of the treatment of opioid-induced constipation. Constipation occurs in up to 50% of individuals taking these drugs, (2, 3) with significant implications for sufferers. These include significantly higher rates of medical consultation and sickness-related work absences, as well as a significantly lower quality of life, compared with opioid users who do not experience constipation. (4) As a result, up to one-third of patients reduce their opioid dosage, or discontinue the drugs altogether, in an attempt to improve their bowel symptoms, negatively impacting on their pain control. (3)
Effective therapies for opioid-induced constipation include the mu-opioid receptor antagonists methylnaltrexone, naloxone, and alvimopan. A recent systematic review and meta-analysis summarised the efficacy of all published placebo-controlled trials of these agents, (5) with numbers needed to treat to prevent one patient failing to respond to therapy of between 3 and 5. Importantly, reversal of analgesia did not occur more frequently with active therapy. These drugs were highly effective, even in patients who had already failed treatment with laxatives, who made up the entire study population in three of the identified trials. Despite this evidence, clear guidelines for the management of opioid-induced constipation from national or international organisations are lacking.
1. Freynhagen R, Geisslinger, G, Schug SA. Opioids for chronic non-cancer pain. BMJ 2013;346:f2937.
2. Cook SF, Lanza L, Zhou X, Sweeney CT, Goss D, Hollis K, Mangel AW, Fehnel SE. Gastrointestinal side effects in chronic opioid users: Results from a population-based survey. Aliment Pharmacol Ther 2008;27:1224-1232.
3. Bell T, Panchal SJ, Miaskowski C, Bolge SC, Milanova T, Williamson R. The prevalence, severity, and impact of opioid-induced bowel dysfunction: Results of a US and European Patient Survey (PROBE 1). Pain Med 2009;10:35-42.
4. Bell T, Annunziata K, Leslie JB. Opioid-induced constipation negatively impacts pain management, productivity, and health-related quality of life: Findings from the National Health and Wellness Survey. J Opioid Manag 2009;5:137-144.
5. Ford AC, Brenner DM, Schoenfeld PS. Efficacy of pharmacological therapies for the treatment of opioid-induced constipation: Systematic review and meta-analysis. Am J Gastroenterol 2013;doi: 10.1038/ajg.2013.169.
Competing interests: No competing interests