Long‐term opioid management for chronic noncancer pain – free full-text /PMC6494200/ – Cochrane Review: Jan 2010
I’ll start with these two key findings in the author’s conclusions from this extremely long Cochrane Review:
1. Many patients discontinue long‐term opioid therapy (especially oral opioids) due to adverse events or insufficient pain relief; however, weak evidence suggests that patients who are able to continue opioids long‐term experience clinically significant pain relief.
2. Whether quality of life or functioning improves is inconclusive. Many minor adverse events (like nausea and headache) occurred, but serious adverse events, including iatrogenic opioid addiction, were rare.
Objective: To assess safety, efficacy, and effectiveness of opioids taken long‐term for CNCP.
We reviewed 26 studies with 27 treatment groups that enrolled a total of 4893 participants.
Signs of opioid addiction were reported in 0.27% of participants in the studies that reported that outcome.
Signs of opioid addiction were reported in 0.27% of participants in the studies that reported that outcome.
All three modes of administration were associated with clinically significant reductions in pain, but the amount of pain relief varied among studies.
Findings regarding quality of life and functional status were inconclusive due to an insufficient quantity of evidence for oral administration studies and inconclusive statistical findings for transdermal and intrathecal administration studies.
The above was the abstract, below are excerpts from the lengthy full text:
Opioids for long‐term treatment of noncancer pain
The findings of this systematic review suggest that proper management of a type of strong painkiller (opioids) in well‐selected patients with no history of substance addiction or abuse can lead to long‐term pain relief for some patients with a very small (though not zero) risk of developing addiction, abuse, or other serious side effects
However, the evidence supporting these conclusions is weak, and longer‐term studies are needed to identify the patients who are most likely to benefit from treatment.
But long term studies are ethically not allowed. It would be unethical to give patients placebos for serious pain for months on end.
However, this doesn’t stop various petty officials from enacting exactly such a study on the American population of pain patients: taking away their pain relief for months and years on end.
So far, the results have been gruesome: tales of tremendous suffering, increased disability, and even suicides to escape the intractable (severe, unrelenting, incurable) pain.
Chronic noncancer pain
In this survey, chronic pain sufferers reported 7 years of chronic pain on average, with some reporting pain lasting more than 20 years.
Although CNCP usually does not arise from an etiology that is inherently life‐threatening, suicide rates are elevated among individuals with chronic pain, especially when there is a sense of hopelessness about the pain (Fishbain 1991; Tang 2006).
The current tight restrictions, enacted as law in many states, have created a pervasive loss of hope of ever achieving significant pain relief again.
One study found that completed suicide was associated with higher pain severity (Kikuchi 2008).
Suicide rates for people with chronic pain remain higher even when mental illness has been accounted for (Ratcliffe 2008).
Opioids for chronic noncancer pain
Although opioid use for acute pain, postsurgical pain, and palliative care is accepted in the United States. and many other countries, there is debate about whether opioids are appropriate for the treatment of CNCP. The efficacy of opioids for CNCP has been demonstrated in short‐term trials
Chronic opioid use (for at least 6 months) has been estimated at 0.65% of a U.S.‐insured population (Cicero 2009), and regular or continuous use has been estimated at 0.27% of Dutch epidemiologic survey respondents (Eriksen 2006). An analysis of insurance database claims in the U.S. found that 10% of people who were prescribed opioids had at least a 3‐month supply (Williams 2008), and the Dutch epidemiologic survey found that 12% of people with pain due to causes other than cancer reported they take opioids “regularly or continuously.”
Participants in all treatment groups reported moderate or severe CNCP at baseline due to nociceptive or neuropathic pain, or both. The most prevalent painful conditions of participants enrolled in the studies were:
The mean duration of pain prior to study enrollment was reported in only 10 studies, but where reported mean durations ranged from 19 months (Rainov 2001) to 10.3 years (Allan 2005). The mean duration of pain prior to enrollment in Rainov 2001 was much shorter than any of the other studies; the next shortest was a duration of pain of 5.3 years (Pimenta 1998), and most studies reported an average duration of pain of about 8 years (Anderson 1999; Klapetek 1971; Kumar 2001; Milligan 2001; Thorne 2008).
In these studies we only considered outcomes for the opioid treatment groups, because long‐term outcomes for the placebo groups were not available.
The scope of this review is to include any opioid administered long‐term. This includes both strong and weak opioids. We used this classification to investigate heterogeneity wherever possible.
Opioids administered in the oral studies [and the duration they were administered for] included the following:
- Extended-release morphine
- Controlled-release oxycodone
- Extended-release oxymorphone
- Extended-release tramadol
- Extended-release oxymorphone
I’m disappointed that even in these “scientific” studies, there is no standard classification of certain opioids as strong and others as weak. This list shows extended-release oxymorphone categorized as strong in some studies and weak in others.
Just as opioid and route of administration varied among studies, so too did dosage. Doses also varied considerably within studies due to individual differences in pain level, opioid tolerance, and titration.
This is how prescriptions should properly be prescribed, based on individual situations, needs, and severity of symptoms.
Risk of bias in included studies
All of the evidence bases considered in this systematic review were of low internal validity and therefore potentially at high risk of bias.
Reasons for low internal validity ratings varied by study, but included
- failure to describe participant recruitment methods;
- failure to compare the characteristics of participants who completed the study to participants who did not in studies with attrition;
- high prevalence of use of ancillary/adjuvant treatments; and
- use of funding from a source with a potential conflict of interest in the outcome.
The risk of bias is probably highest for the continuous outcomes (e.g., pain relief, quality of life)…
Exactly the most important factors for real patients.
…and lowest for the outcomes on discontinuation from clinical study and adverse events.
This is primarily because the high attrition rates affect both the risk of bias and the generalizability of the results from the continuous data outcomes
We attempted to minimize selection bias by requiring prospective studies, but this may still be a threat, particularly to open‐label continuations of RCTs.
Effects of interventions
The first outcome we present is adverse events, because many clinicians and patients are particularly concerned about the harms associated with opioids.
We then present an assessment of discontinuation rates for the two most common reasons cited for leaving a study (adverse events and insufficient pain relief) before analyzing effectiveness outcomes.
In all the opioid studies I’ve read (seems like hundreds by now), I have never seen one word about insufficient pain relief, probably because the quality of “pain relief” wasn’t measured because it relies on the subject’s perceptions, not some measurable quality.
The rate of discontinuation from a clinical study represents the number of participants who discontinued participation in the study. The rate does not necessarily capture the rate of discontinuation of opioids. Participants may continue opioids under different protocols, change opioids, or change mode of administration.
The fact that such unexpected outcomes are never mentioned shows they are usually disregarded and folded into the other discontinuations.
In the one study that tracked satisfied departures, 87% of enrollees who discontinued participation left as satisfied departures, and at 48 months, 92% of enrollees were either still in the study or had a satisfied departure (Mystakidou 2003).
The findings of this study suggest that high attrition is not necessarily synonymous with high rates of treatment failure.
Yet, those that quit the study are assumed to have “failed”.
This would happen in a study about tapering. Many subjects would simply drop out when their pain becomes too great and keep taking opioids.
The variability in thresholds for reporting adverse events, failure to report whether certain adverse events occurred in some studies, and inconsistent reporting or use of definitions of events/effects precluded our ability to pool data in meta‐analyses to determine rates. Absence of long‐term nonopioid control groups precluded determination of relative rates of adverse events.
Adverse events (side effects)
The most commonly reported adverse events included
- gastrointestinal effects (i.e., constipation, nausea, dyspepsia),
- fatigue/lethargy/somnolence, and
- urinary complications (i.e., retention, hesitancy, ”disturbance”)
Most of the adverse events were minor.
Six studies specifically stated that no cases of addiction were observed, and 18 studies did not report whether addiction was observed
In one prospective registry study in which participants were pre‐screened for addiction and abuse, six (3%) appeared to meet criteria for opioid abuse and/or addiction as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM‐IV)
Among the studies where addiction or addiction and abuse rates are specifically reported, the total event rate is 0.27% (7/2613).
This truth is cleverly hidden, buried in this paper but never announced and exposed like the overdose deaths.
Two of the studies reported a total of 10 deaths. Eight participants in one study died within one year of beginning oral opioids for reasons that were not reported, suggesting that these deaths were not opoid‐related.
The study authors reported that no serious opioid‐related adverse events occurred (Zenz 1992). In the other study, one death was attributed to an automobile accident and another to suicide (Pascual 2007).
Five studies that examined the impact of transdermal opioid administration and enrolled a total of 1626 participants provided adverse events data.
An adverse event that only occurred with transdermal administration was skin irritation at the application site.
One study reported nine deaths, of which one, due to severe bronchopneumonia, was considered possibly attributable to transdermal opioids (Milligan 2001). The authors did not believe that the other eight deaths were opioid‐related.
Adverse events were extracted from 10 studies on intrathecal opioid administration that enrolled a total of 228 participants. Adverse events unique to the intrathecal mode of administration included pump and catheter malfunctions and malpositioning, surgical complications, and postsurgical complications.
In one study, the deaths were due to chronic obstructive pulmonary disease (n = 1), pericolonic abscess (n = 1), and myocardial infarction (n = 1) (Anderson 1999). In the other study, deaths were due to suicide (n = 1), myocardial infarction (n = 1), and an unknown cause (n = 1)
Discontinuation from clinical study due to adverse events
Duration of treatment, which ranged widely from about six to eight months (Caldwell 2002; Harati 2000; Rauck 2008; Thorne 2008; Zenz 1992) to about two years (Portenoy 2007), was not observed to be associated with the outcome. Year of study publication, drug administered, sample size, and cause of pain were not associated with the outcome either.
Discontinuation from clinical study due to insufficient pain relief
The same 10 studies that comprised the evidence base for rate of discontinuation due to adverse events also reported the rate of discontinuation due to insufficient pain relief.
The pooled rate of discontinuation due to insufficient pain relief was 10.3% (95% CI: 7.6% to 13.9%), as shown in Figure 4.
Combined in meta‐analysis, the overall proportion of participants who discontinued study participation due to insufficient relief was 5.8% (95% CI: 4.2% to 7.9%). This is illustrated in Figure 5
Six studies with 113 participants with mostly failed back surgery syndrome or neuropathic pain reported on the proportion who discontinued participating in the study due to insufficient pain relief
The summary rate ofdiscontinuation due to insufficient pain relief was 7.6% (95% CI: 3.7% to 14.8%).
This means that almost a tenth of patients never achieved enough pain relief to make opioids worthwhile for them.
Studies always insinuate that “opioids didn’t work” for these patients, and ignore the other obvious possibility: doses weren’t titrated high enough to be effective.
There is no fixed upper limit to dose, though politically expedient hard limits have been used to create scientifically and medically invalid restrictions.
Use of the standardized mean differences (SMD) allowed these studies to be combined in a meta‐analysis; however, the variation among instruments precludes translation of the pooled estimate into a single original metric.
We pooled data at 6 to 7.5 months to promote comparability of the data, because this was the only duration of follow‐up for which all three studies reported data
Interpretation of the average amount of pain relief this represents in the original metric to attempt to determine whether the effect size is indeed large enough to be clinically significant is not possible, because three different pain scales were used.
However, this SMD would be considered to represent a medium to large treatment effect between independent groups. More importantly, considered in isolation, each study suggests a clinically important reduction in pain from baseline.
Although all four studies reported significant reductions in pain among completers, they varied with respect to just how much pain reduction was achieved.
Because of the unexplained heterogeneity and lack of quantitative robustness, we believe the summary estimate may not accurately represent the average amount of pain relief among people able to continue opioids for about six months
However, because all four studies consistently show at least a moderate reduction in pain from baseline, and because this qualitative conclusion was robust to all sensitivity analyses, we conclude that pain relief that appears to be clinically important is achieved long‐term for patients able to remain on oral opioids for six months.
Proportion of participants with at least 50% pain relief
Two studies with a total of 442 participants reported the proportion of participants who attained at least 50% pain relief on oral opioids
One hundred thirty four (39%) participants in Allan 2005 and 51 participants (51%) in Zenz 1992 were reported to have at least 50% pain relief with long‐term opioid administration. Overall, 44.3% (95% CI: 33.3% to 55.9%) of participants had at least 50% pain relief, as shown in Figure 8.
Two studies that administered transdermal fentanyl to participants with various chronic painful conditions reported long‐term pre‐post pain scores (Collado 2008; Mystakidou 2003). A total of 744 participants were enrolled in these studies.
Large reductions in pain were reported in both studies, with participants reporting severe pain at baseline (combined mean pain score 8.58, 95% CI: 6.07 to 11.09) and mild pain after six months of treatment (combined mean pain score 1.87, 95% CI: 1.53 to 2.21)
these studies suggest that clinically significant pain relief is attained on average among patients who begin transdermal fentanyl for CNCP. This finding was robust to all sensitivity analyses but supported by weak evidence.
Proportion of patients with at least 50% pain relief
One hundred and twenty nine (38.2% [95% CI: 33.1% to 43.5%]) participants had a 50% or greater reduction in pain during the course of the study.
Nine studies that enrolled a total of 220 participants with CNCP due to a variety of causes, most frequently failed back surgery syndrome, reported pre‐ and post‐treatment pain scores
Importantly, when considered in isolation, each study shows clinically significant mean reductions in pain among the participants remaining in the study for long‐term follow‐up.
Although the studies consistently showed significant pain relief when considered individually, analysis revealed substantial heterogeneity in the amount of pain relief among the studies.
This is exactly why our doctors should individualize opioid therapy and why any arbitrary limits will restrict some patients from ever achieving significant pain relief.
Predominant cause of pain was the only factor significantly associated with the SMD.
- Failed back surgery syndrome (k = 5) was associated with the least amount of pain relief,
- unspecified (k = 2) and neuropathic pain (k = 1) were associated with more pain relief, and
- osteoporotic vertebral fractures (k = 1) were associated with the most pain relief.
However, these data consistently show that participants experienced clinically significant pain relief with long‐term administration of opioids by an implantable infusion pump, and although supported by weak evidence, this finding is robust.
Proportion of patients with at least 50% pain relief
Seven studies that enrolled a total of 151 participants were included for this analysis.
The summarized proportion of participants who had at least a 50% reduction in pain was 44.5% (95% CI: 27.2% to 63.2%), which is shown in Figure 12.
However, year of study publication was, with more recently published studies showing larger proportions of participants with at least 50% pain relief.
Many participants in the included studies, particularly those treated with orally‐administered opioids, were so dissatisfied with adverse events or insufficient pain relief that they discontinued participating in the studies.
As no data are provided on these participants after they dropped out of the studies, it is impossible to say whether they continued opioid therapy under different protocols.
Yet, anti-opioid zealots always assume that any dropouts dropped out because “opioids didn’t work for them”.
For participants able to continue opioids in the studies, evidence (albeit weak) suggests that, for all analyzed modes of administration, their pain scores were lower on average than before therapy began, and that this relief could be maintained long‐term (> 6 months).
An evidence base consisting of low‐quality studies provides only weak evidence from which to draw qualitative conclusions and only low‐stability evidence from which to draw quantitative conclusions.
Among outcomes for which qualitative conclusions were possible, unexplained heterogeneity limited the number of quantitative conclusions we could make.
For discontinuation from the study due to adverse events or insufficient pain relief, this may be because most people who discontinue participation in opioids studies do so within the first six months.
For pain, this may be because optimum pain relief is achieved within six months and longer durations of treatments serve to maintain the effect, or it may be because participants with the most treatment‐resistant pain discontinue participating in the study early on.
The high attrition rates in some of the studies call into question whether the participants reporting continuous outcomes are representative of the patient population originally enrolled in those studies, and whether as a result, this attrition is a threat to internal or external validity.
This is a common problem of all studies evaluating the effectiveness of medications: when significant numbers of participants drop out, this can skew the “randomness” of the rest of the group still being studied.
For instance, if participants with more significant pain dropped out due to insufficient pain relief (doses not high enough?) and are not further tracked, the study is left with a group that doesn’t have many high-pain participants. This is then no longer a “random” group which invalidates the results for the originally “randomly assigned” group.
For oral opioids in particular, findings on amount of pain relief or change in quality of life strictly pertain to the participants remaining at longer durations of treatment, and do not necessarily indicate the average treatment effect for all patients who begin oral opioids.
Measuring the proportion of participants who had clinically significant pain relief circumvented the problem of attrition, because individuals who dropped out of the study were assumed to be treatment failures.
And this is the mother of all invalid assumptions that keeps coming up among those that insist opioid treatment “doesn’t work” for chronic pain.
Control groups are essential when patients’ future outcomes are highly uncertain. However, if the natural history of a disease is stable, substantive improvement would not be expected without the intervention in question.
As patients prescribed long‐term opioids have had pain long‐term, and have typically experienced failure of more conservative treatment options (e.g., simple analgesics, physical therapy),
many have had a lack of success with surgery (e.g., patients with failed back surgery syndrome).
This is very interesting and goes against what we’re being told about our pain relief being due only to placebo effects.
So many of us had complete faith in the interventions we tried and only reluctantly had to concede their failure. If the placebo effect were significant for pain, our pain should have been relieved when we started the first intervention attempt.
Instead, I and so many others have been disappointed time and time again.
I used to believe in “alternative medicine” and tried mightily to find pain relief from each one of them. I spent my rapidly dwindling money and hope on countless “alternative” interventions but my stubbornly persistent pain has shattered those hopes.
Treatments I (and my doctors) fully expected to be effective proved useless.
Below is the full section of the author’s conclusions:
Most of the participants in these studies had back pain, often following failed back surgery, osteoarthritis, or neuropathic pain.
These findings should not be generalized to patients with chronic pain of other types, such as headache.
This is another point glossed over by anti-opioid doctors and even scientists: chronic pain is not a monolithic condition. Studies focused on one kind of pain can never be generalized to other kinds.
Just like there’s no single type of sickness, there’s no single type of chronic pain, yet that’s exactly what all these studies assume.
The same scientists that would laugh at a study that finds aspirin eases “sickness”, would take seriously a study that aspirin eases “pain”.
Concern that an individual with CNCP may develop dependence on the drug during long‐term administration represents a potential barrier to treatment. However, the rate of observed signs of opioid addiction was extremely low in the body of evidence considered in this review (0.27%, conservatively).
This rate would be 0.14% if no addictive behaviors occurred among the studies that did not mention addiction rates at all.
Only three participants were reported as having potential abuse problems.
These numbers do not support the contention that potential iatrogenic opioid addiction should limit therapy for well‐selected and well‐supervised patients.
Again, it becomes clear that substance abuse isn’t a common outcome of legitimately prescribed opioid medication.
This finding is consistent with that of another review article on opioid abuse and addiction that calculated an abuse/addiction rate of 0.19% in studies that prescreened chronic pain patients for long‐term opioid use or addiction/abuse history, and 3.27% in all studies (Fishbain 2008).
Given the complexity of definitively diagnosing opioid addiction (see Ballantyne 2006)
Yet it’s usually, and wrongly, assumed that anyone using opioids long-term has SUD or addiction.
The Mayday Fund (www.maydayfund.org), a foundation sponsoring pain treatment research, asked ECRI Institute to review issues including the efficacy and safety of opioids for noncancer pain in 2004.
The Milbank Memorial Fund (www.milbank.org) invited an international group of pain researchers to help formulate key questions. Representatives from these organizations and additional pain researchers critiqued the review and made recommendations for future research.
Allowing rescue opioids (with the amount and frequency of dosage as an outcome) in placebo or nonopioid groups may circumvent ethical problems of withholding treatment from individuals with CNCP in long‐term RCTs.
Protocols should specify uniform diagnostic and data collection criteria (e.g., pain etiology, drugs prescribed, dosing regimens) and mimic clinical practice (e.g., drug combinations could be used, drug changes could be made, drug dosage could be titrated slowly and adjusted, adverse effects could be aggressively managed).
Without information on the source of pain, all these studies are comparing different things and using the numbers as “generally applicable “ when in reality, the effects would vary substantially. Without this information, we cannot assume any generalizations.
Reasons for discontinuation, including satisfied departures, must be documented.
Long‐term poorly‐understood effects, including androgen deficiency and changes in immune function, must be documented.
However, practical/pragmatic RCTs might be cost prohibitive (Tunis 2003). Adequately powered, well‐designed prospective cohort studies could provide useful information (Geborek 2002; MacDonald 2003; Mamdani 2002).
Long‐term dose‐dependent efficacy and adverse effects could be researched in existing databases (e.g., European Medicines Evaluation Agency, FDA, Australia Therapeutic Goods Administration).
Despite the identification of 26 treatment groups with 4768 participants, the evidence regarding the effectiveness of long‐term opioid therapy in CNCP is too sparse to draw firm conclusions, including quantity of mean of pain relief.
Yet, anti-opioid zealots claim these studies prove that opioids don’t work for chronic pain and lead to addiction.
- First of all, “the evidence is too sparse to draw firm conclusions” applies to all studies, both those supporting and those condemning opioid use.
- Secondly, the absence of evidence is not evidence of absence. Even if studies don’t find evidence of significant pain relief, this is not evidence that there is none.
Poor reporting reduced the amount of acceptable data.
Because many studies on opioids are intended and designed (and funded) to find negative outcomes from opioids, there are few provisions to track positive outcomes, like pain relief or gains in functionality, with the same meticulous care as negative ones.
When researchers are so determined to find problems with opioids, results leaning toward other conclusions are muddled and buried in “poor reporting”.
Studies should always report data needed for meta‐analysis (mean, standard deviation, number of participants, or data to calculate them), and authors of studies for which these data were not originally published should consider making them publicly available.
Studies should also
- use validated scales,
- report intention‐to‐treat data in addition to completer analyses, and
- conduct post‐hoc analyses to identify prognostic factors for treatment success.
The lack of such measures seems a clear indication of studies whose results didn’t match their desired outcome.