Long-term opioid treatment of chronic nonmalignant pain: unproven efficacy and neglected safety?

Figures & data

Figure 1 Flow chart of screened, excluded, and included articles on chronic nonmalignant pain from 1983–2012.

Abbreviation: RCT, randomized controlled trial.

Table 1 Duration of opioid treatment in studies on chronic nonmalignant pain

Duration of treatment	Number of studies without a proper control group*,^Citation11^–^Citation38				Number of randomized controlled trials^Citation39^–^Citation63
	≤1 m	>1 m–<3 m	≥3 m	≥1 y	≤1 m	>1 m–<3 m	≥3 m	≤1 y
Years
1983–1992	1	0	0	3	1	0	0	0
1993–2002	4	1	2	6	10	2	0	0
2003–2012	4	0	3	4	5	6	1	0
Total	9	1	5	13	16	8	1	0

Note:

* Studies without a proper control group (see Grimes and Schulz).⁶⁴

Abbreviations: m, month; y, year.

Table 2 Studies with the duration of opioid treatment ≥6 months

Reference	Study design	Diagnosis	Opioid	Route of administration	Number of enrolled patients	Length of treatment
France et al^Citation11	Case series (uncontrolled, retrospective, selected patients)	Back pain	Codeine, oxycodone, hydromorphone	Oral	16	6–22 months
Portenoy and Foley^Citation12	Descriptive study (uncontrolled, retrospective, patients selected from two separate studies)	Back pain, postherpetic neuralgia, neuropathic pain	Oxycodone, methadone, levorphanol, codeine	Oral	38	6 months to 10 years
Zenz et al^Citation13	Descriptive study (uncontrolled, prospective)	Back pain, neuropathic pain	Sustained-release dihydrocodeine, buprenorphine, sustained-release morphine	Oral	100	≥ 1 year (20 patients)
Kanoff^Citation15	Descriptive study (uncontrolled, prospective)	Reflex sympathetic dystrophy, arachnoiditis	Morphine via implanted delivery system	Intrathecal	15	2–44 months
Hassenbusch et al^Citation16	Descriptive study (uncontrolled, prospective)	Neuropathic pain	Morphine, sufentanil via implanted delivery system	Intrathecal	22	12–56 months (18 patients)
Tutak and Doleys^Citation17	Descriptive study (uncontrolled, prospective)	Back pain	Morphine via implanted delivery system	Intrathecal	26	16–27 months
Angel et al^Citation19	Descriptive study (uncontrolled, prospective)	Back pain, neuropathic pain	Morphine via implanted delivery system	Intrathecal	15	3 years(11 patients)
Anderson and Burchiel^Citation20	Descriptive study (uncontrolled, prospective)	Neuropathic pain, nociceptive pain	Morphine via implanted delivery system	Intrathecal	40	24 months (20 patients)
Harati et al^Citation24	Descriptive study (uncontrolled, prospective)	Diabetic neuropathy	Tramadol	Oral	117	6 months (100 patients)
Milligan et al^Citation25	Descriptive study (uncontrolled, prospective)	Neuropathic pain, nociceptive pain	Fentanyl	Transdermal	532	12 months (301 patients)
Mironer and Tollison^Citation26	Descriptive study (uncontrolled, prospective)	Back pain, neuropathic pain	Methadone	Intrathecal	24	6 months (9 patients)
Anderson et al^Citation28	Uncontrolled study (prospective, randomized to morphine intrathecal infusion or its epidural injection)	Chronic nonmalignant pain	Morphine via implanted delivery system	Intrathecal	40	6 months (27 patients)
Allan et al^Citation31	Uncontrolled study (prospective, multicenter, randomized to oral morphine)	Back pain	Fentanyl	Transdermal	680	13 months
Chao^Citation32	Descriptive study (uncontrolled, retrospective)	Back pain, neuropathic pain	Sustained-release morphine	Oral	68	12 months
Mcllwain and Ahdieh^Citation33	Descriptive study (uncontrolled, prospective, multicenter)	Osteoarthritis	Extended-release oxymorphone	Oral	153	12 months (61 patients)
Portenoy et al^Citation36	Uncontrolled registry study	Osteoarthritis, diabetic neuropathy, back pain	Controlled-release oxycodone	Oral	219	1–3 years (14–39 patients)

Table 3 Systematic reviews on opioid treatment of chronic pain

Study	Type of pain	Opioid	Route of administration	Duration of treatment	Conclusion on the treatment efficacy
Kalso et al^Citation6	Osteoarthritis, diabetic neuropathy, peripheral neuropathic pain, phantom limb pain, postherpetic neuralgia, musculoskeletal pain	Morphine, oxycodone	Oral, transdermal, or intravenous	From 4 days to 8 weeks	The short-term efficacy of opioids was good in both neuropathic and musculoskeletal pain conditions. However, only a minority of patients went on to long-term management with opioids; therefore, open-label follow-up data were too weak to make a definite conclusion.
Martell et al^Citation7	Back pain	Morphine, oxycodone, sustained-release morphine, controlled-release oxycodone, other opioids	Oral or transdermal	From 7 days to 16 weeks	Opioids may be efficacious for short-term pain relief. Long-term efficacy was unclear.
Noble et al^Citation8	Neuropathic pain, osteoarthritis, back pain	Morphine, tramadol, methadone, controlled-release oxycodone, extended-release oxymorphone, fentanyl, sufentanil, dihydrocodeine, buprenorphine	Oral, transdermal, or intrathecal	From 6–48 months	Weak evidence suggests that oral and intrathecal opioids reduce pain long-term in the relatively small proportion of individuals who continue treatment.
Nuesch et al^Citation9	Osteoarthritis	Codeine, morphine, oxycodone, oxymorphone	Oral or transdermal	From 3 days to 3 months	The small to moderate beneficial effects of opioids are outweighed by large increases in the risk of adverse events. Therefore, opioids should not be routinely used, even if osteoarthritic pain is severe.

Table 4 Editorials on opioid addiction in chronic pain patients

Years	Number of editorials
	“Addiction”a AND “chronic pain”b	“Addiction”a
1973–1982	–	12
1983–1992	0	19
1993–2002	1c	63
2003–2012	4d	171

Notes:

a OR “dependence” OR “abuse” OR “misuse;”

b OR “neuropathic pain” NOT (“cancer pain” OR “terminal illness”);

c reference 66;

d references 67–70.

Table 5 Articles on opioid addiction in chronic pain patients in the top 20 journalsa

Years	Number of articles
	“Addiction”b AND “chronic pain”c	“Addiction”b
1973–1982	–	5
1983–1992	1d	5
1993–2002	0	12
2003–2012	5e	40

Notes:

a List of top journals: Addiction, The American Journal of Psychiatry, Annals of Internal Medicine, Annals of Neurology, Archives of General Psychiatry, BMJ, The Journal of Clinical Investigation, The Journal of Pharmacology and Experimental Therapeutics, JAMA: The Journal of the American Medical Association, Lancet, The New England Journal of Medicine, Nature Medicine, Nature Neuroscience, Nature Reviews Drug Discovery, Nature Reviews Neuroscience, Nature, Pharmacological Reviews, Proceedings of the National Academy of Science of the United States of America, Science (New York, NY, USA), and Trends in Pharmacological Sciences;

b OR “dependence” OR “abuse” OR “misuse;”

c OR “neuropathic pain” NOT (“cancer pain” OR “terminal illness”);

d reference 73;

e references 74–78.

Table 6 Topic-in-title articlesa on opioid addiction in chronic pain patients

Years	Number of articles
	“Addiction”b AND “chronic pain”c	“Addiction”b
1973–1982	–	893
1983–1992	2d	536
1993–2002	13e	628
2003–2012	51f	1,404

Notes:

a Articles with titles clearly indicating that they are devoted to the addiction in chronic pain patients

b OR “dependence” OR “abuse” OR “misuse”

c OR “neuropathic pain” NOT (“cancer pain” OR “terminal illness”)

d references 79–80

e references 81–93;

f references 94–144.

Table 7 Topic-in-title articlesa on death associated with opioid addiction in chronic pain patients

Years	Number of articles
	“Death”b AND “addiction”c AND “chronic pain”d	“Death”b AND “addiction”c
1973–1982	–	4
1983–1992	0	3
1993–2002	0	2
2003–2012	4e	4

Notes:

a Articles with titles clearly indicating that they are devoted to death associated with addiction in chronic pain patients;

b OR “mortality” OR “fatality;”

c OR “dependence” OR “abuse” OR “misuse;”

d OR “neuropathic pain” NOT (“cancer pain” OR “terminal illness”);

e references 145–148.

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