longterm efficacy of opioids for chronic pain

an independent study (sponsored by Agency for Healthcare Research and Quality, for an NIH workshop) did a very thorough systematic review of the effectiveness and risks of long-term opioids for chronic pain (see opioids and long term efficacy chr pain annals 2015 in dropbox, or Ann Intern Med. 2015;162:276-286​), where chronic pain is defined as lasting longer than 3months or beyond the normal time for tissue healing. they acknowledge that chronic pain is common and associated with decreased quality of life and with disability. and they note that there has been a dramatic increase in opioid med prescriptions, with attendant increases in overdose, abuse, addiction and diversion.  their findings:

--Long-term effectiveness of opioids: "No study of opioid therapy versus placebo, no opioid therapy, or nonopioid therapy evaluated long-term (>1 year) outcomes related to pain, function, or quality of life"  (and that is all they say about effectiveness)

--Harms: (not great data, at best "fair quality" studies) 

        -- from large insurance company claims data, rates of opioid abuse or dependence were increased in those on long-term opioid therapy (>90 days) and varied from 0.7% in those on low dose (morphine-equivalent doses [MED] of 1-36 mg/d) to 6.1% with high-dose therapy (MED > 120 mg/d), vs 0.004% in those on no opioids

        --in pain clinic setting, prevalence of misuse ranged from 8-16%; prevalence of addiction from 2-14%

        --prevalence of aberrant drug-related behaviors (eg aberrant urine drug tests, medication agreement violations), ranged from 6-37%. and especially in those with history of substance use disorder, younger age, major depression and use of psychotropic medications

        --overdosage: increase in "any overdose event" in those with recent opioid use, with annual rate of 256/100K person-years vs 36/100K person-years in those not prescribed

        --fractures: higher fracture rate in opioid users (6% vs 4%, with another study finding a 27% increase in hip, humerus or wrist fractures, but this was not dose-dependent; highest risk was with one prescription, decreased with more)

        --cardiovascular events: several studies found increase in myocardial infarction in opioid users of >3 months, with increases being dose-dependent

        --endocrinologic events: opioids associated with increased male erectile dysfunction, especially at higher doses [and, by the way, this has been the major issue leading a few of my patients to stop opioids!!]

        --motor vehicle accidents: people on MEDs of at least 20 mg/d had more traffic accidents

--Opioid dosing strategies:

        --initiation of sustained- vs immediate release opioids: inconsistent results of which approach was better

        ​--comparison of different long-acting opiates: again, not great trials. of interest, a VA trial of methadone vs long-acting morphine found a lower risk of death with methadone (a tad surprising, given the increase in QTc intervals with methadone, and the high MED equivalents, with 1 mg methadone being equivalent to 3 mg of morphine). but generally no difference between the long-acting preparations in terms of 1-year pain or function outcomes

        --dose escalation: the one trial which really looked at this with 140 patients, comparing more liberal dose escalations vs maintaining the current dose after 12 months, found no differences, but there was only a 52 MED vs 40 MED difference between the groups

        -- and no study compared the effectiveness of long-acting opioids vs short-acting; short plus long-acting vs just long-acting; scheduled dosing vs prn dosing; or opioid rotation vs maintaining current therapy.

so, in summary, this comprehensive systematic review found a few things: almost all of the studies were of fair to poor quality (eg, mostly observational, retrospective, and I bet there were lots of differences between the patients given opioids and those on other meds, and between those on high vs low dose opioids), and none really addressed the essential clinical questions noted in the above systematic review that we have in primary care (or pain management clinics, for that matter).  but it is important to keep in mind that the lack of evidence of effectiveness does not mean that opioids, even at high doses, are ineffective.  i suspect that most of us have seen patients who have "real" chronic pain, take their medications appropriately, and do benefit from increasing and sometimes very high doses of opiates. but there are no studies to confirm this: none have titrated patients to differing doses of meds, in an RCT, to assess the associated benefits and risks (and for many patients, they will willingly tolerate the potential risks in order to get pain relief).  a few other points:

--the underlying issue here is that there was a large push to treat pain aggressively (pushed by the Institute of Medicine and reinforced by the lobbying of Purdue, makers of oxycontin, to establish pain as the "5th vital sign").  this led many clinicians (myself included) to prescribe opioids more freely, as well as titrate up the dose as needed in an attempt to fully relieve that pain. but, alas, this was, it turns out, based on no scientific data (as clear from the above systematic review), is clearly associated with adverse effects on patients, and is generally bad for society (esp through diversion, availability of prescription opiates in the street, and the associated morbidity and mortality of prescription opiate abuse). For prior blogs on this issue see, for example, 

http://blogs.bmj.com/ebm/2014/07/09/primary-care-corner-with-geoffrey-modest-md-chronic-pain-yet-again/ , but there are several others as well in the category “pain/opiates” on the website and in the dropbox in "chronic pain" folder.

--A study done in the Group Health Cooperative in Washington looked at the association between opioid dosing and overdoses: they found that in 9940 patients receiving 3 or more opioid prescriptions within 90 days for noncancer pain, there were 51 overdoses (6 fatal), with 0.2% annual rate in those on 1-20 mg/d MED, a 3.7-fold increase in those on 50-99 MED and a 8.9-fold increase in those on >100 MED (see opioids chronic pain and OD annals 2010​ in dropbox, or Ann Intern Med. 2010;152:85-92), though by our current standards, these people were on smaller doses (mean of 13.3 MED) than we are seeing now. so, in this study of 17,582 person-years of taking opiates, only 614 were in those taking >100 MED and 886 were in those taking 50-100 MED. and, again, this is a retrospective study with its inherent and likely large biases.

--another study from Washington found that implementation of a guideline requiring patients on MEDs > 120 mg/d to have a reassessment or consultation did find a decrease in opioid-associated overdose deaths (see Am J Med. 2012; 55:325-31).

--but the frequent experience we have is that trying to decrease doses of opiates leads to patient dissatisfaction, sometimes hostility, and is the antithesis of what we are trying to do in primary care: develop a therapeutic bond with patients wherein both providers and patients feel that we are working together to better the health and well-being of patients (there are patients who are willing to decrease the level of opiates after some education, but our experience is that this is quite unusual). 

--and, one side issue, is that the patients who have been on high-dose opiates now for many years, are now older, metabolize the drugs less efficiently, and may be at even higher risk for adverse effects.  

--so, lacking data, what is one to do?? the short answer is: i really don't know. i do try to decrease opioid dosages in those on very high doses because of concern about potentially very serious adverse effects and the increased potential of social harm through diversion (which may be from a family member and not the patient him/herself); and occasionally I have had some great success without significantly destroying my relationship with the patients. and i will continue to do so, since there are clearly adverse patient and social effects of prescribed opiates. but, given how common this problem of treating chronic pain is, there really should be longer term studies of efficacy of opiates in chronic pain and the appropriate dosing. (i do realize that every editorial ends with "and there should be further studies....", but this is really a huge lacune in our knowledge)