Attitudes Towards and Management of Opioid-induced Hyperalgesia: A Survey of Chronic Pain Practitioners

Abstract

Objectives:
Opioid-induced hyperalgesia (OIH) is a phenomenon whereby opioids increase patients' pain sensitivity, complicating their use in analgesia. We explored practitioners' attitudes towards, and knowledge concerning diagnosis, risk factors, and treatment of OIH.

Methods:
We administered an 18-item cross-sectional survey to 850 clinicians that managed chronic pain with opioid therapy.

Results:
The survey response rate was 37% (318 of 850). Most respondents (240 of 318, 76%) reported they had observed patients with OIH in their practice, of which 38% (84 of 222) reported OIH affected >5% of their chronic pain patients. The majority (133 of 222, 60%) indicated that OIH could result from any dose of opioid therapy. The most commonly endorsed chronic pain conditions associated with development of OIH were fibromyalgia (109 of 216, 51%) and low back pain (91 of 216, 42%), while 42% (91 of 216) indicated that no individual chronic pain condition was associated with greater risk of OIH. The most commonly endorsed opioids associated with development of OIH were oxycodone (94 of 216, 44%), fentanyl (86 of 216, 40%), and morphine (84 of 216, 39%); 27% (59 of 216) endorsed that no specific opioid was more likely to result in OIH. Respondents commonly managed OIH by opioid dose reduction (147 of 216, 68%), administering a non-opioid adjuvant (133 of 216, 62%), or discontinuing opioids (95 of 216, 44%).

Discussion:
Most clinicians agreed that OIH is a complication of opioid therapy, but were divided regarding the prevalence of OIH, etiological factors, and optimal management.

Full text

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Attitudes Towards and Management of
Opioid-induced Hyperalgesia
A Survey of Chronic Pain Practitioners
Elena Kum,*†‡ Norman Buckley, MD, FRCPC,†‡
Oscar de Leon-Casasola, MD,§ Mark Lema, MD, PhD,§
and Jason W. Busse, DC, PhD†‡∥¶
Objectives: Opioid-induced hyperalgesia (OIH) is a phenomenon
whereby opioids increase patients’pain sensitivity, complicating their
use in analgesia. We explored practitioners’attitudes towards, and
knowledge concerning diagnosis, risk factors, and treatment of OIH.
Materials and Methods: We administered an 18-item cross-sectional
survey to 850 clinicians that managed chronic pain with opioid
therapy.
Results: The survey response rate was 37% (318/850). Most
respondents (240/318, 76%) reported they had observed patients
with OIH in their practice, of which 38% (84/222) reported OIH
affected >5% of their chronic pain patients. The majority (133/222,
60%) indicated that OIH could result from any dose of opioid
therapy. The most commonly endorsed chronic pain conditions
associated with the development of OIH were fibromyalgia (109/
216, 51%) and low back pain (91/216, 42%), while 42% (91/216)
indicated that no individual chronic pain condition was associated
with greater risk of OIH. The most commonly endorsed opioids
associated with the development of OIH were oxycodone (94/216,
44%), fentanyl (86/216, 40%), and morphine (84/216, 39%); 27%
(59/216) endorsed that no specific opioid was more likely to result in
OIH. Respondents commonly managed OIH by opioid dose
reduction (147/216, 68%), administering a nonopioid adjuvant (133/
216, 62%), or discontinuing opioids (95/216, 44%).
Discussion: Most clinicians agreed that OIH is a complication of
opioid therapy, but were divided regarding the prevalence of OIH,
etiological factors, and optimal management.
Key Words: chronic pain, opioid-induced hyperalgesia, primary care
(Clin J Pain 2020;36:359–364)
The use of opioids for the treatment of chronic pain may
lead to opioid-induced hyperalgesia (OIH), a state of
sensitization plasticity resulting in pronociception due to
exposure to opioids.1,2 Patients prescribed opioids for
chronic pain may paradoxically experience heightened sen-
sitivity to noxious stimuli, limiting the clinical utility of
opioids in providing effective analgesia.
Preclinical studies provide evidence for the development
of OIH in animal models, implicating spinal dynorphins, the
central glutamatergic system, genetics, descending facilitation,
and enhanced nociceptive response.1,3 OIH has been docu-
mented in patients exposed to opioids in the acute perioperative
period, and in healthy volunteers who have been acutely
exposed to opioids.1,4,5 Increased risk for OIH has also been
demonstrated in former opioid addicts who are on methadone
maintenance therapy.1,6–8Evidence is mixed for the develop-
ment of OIH in adults with chronic pain undergoing long-term
opioid therapy, and detection may be influenced by the
assessment measure used.9,10 Symptoms of OIH include
increased sensitivity to pain, diffuse pain, and allodynia, which
may overlap with opioid tolerance, withdrawal, addiction, and
physical dependence.1,11 Lack of consensus regarding the defi-
nition of OIH, and challenges in distinguishing this condition
from opioid tolerance, have generated controversy among
practitioners regarding its clinical relevance.
A 2011/2012 survey explored physicians’clinical
interpretation of OIH versus opioid tolerance but did not
restrict respondents to clinicians who managed chronic pain
with opioid therapy, was not pretested before administration,
and suffered from a low response rate (14%; 201/1408).12 To
address these limitations, we surveyed a group of predom-
inantly US and Canadian clinicians who managed chronic
pain patients with opioid therapy to determine their attitudes
towards, and knowledge concerning diagnosis, risk factors,
and treatment of OIH.
MATERIALS AND METHODS
Questionnaire Development
With the assistance of anesthesiologists, epidemiologists,
and review of a prior survey,12 we developed an 18-item,
English language questionnaire to examine attitudes and
practices regarding OIH among clinicians managing chronic
pain with opioid therapy (Appendix 1, Supplemental Digital
Content 1, http://links.lww.com/CJP/A634). Survey items
included: (1) clinical features of OIH; (2) management of
OIH; (3) chronic pain conditions perceived to be associated
with the development of OIH; (4) opioids believed to be
implicated in OIH; and (5) the association of opioid dose and
Received for publication May 28, 2019; revised December 18,
2019; accepted January 16, 2020.
From the *Faculty of Science, Western University, London; Depart-
ments of †Anesthesia; ∥Health Research Methods, Evidence and
Impact; ‡Michael G. DeGroote Institute for Pain Research and
Care; ¶Canadian Veterans Chronic Pain Centre of Excellence,
McMaster University, Hamilton, ON, Canada; and §Department of
Anesthesiology, Roswell Park Cancer Institute, Buffalo, NY.
The authors declare no conflict of interest.
Reprints: Norman Buckley, MD, FRCPC, Department of Anesthesi-
ology, McMaster University, 1280 Main Street West, Hamilton,
ON, Canada L8S 4L8 (e-mail: buckleyn@mcmaster.ca).
Supplemental Digital Content is available for this article. Direct URL
citations appear in the printed text and are provided in the HTML
and PDF versions of this article on the journal’s website, www.
clinicalpain.com.
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/AJP.0000000000000814
ORIGINAL ARTICLE
Clin J Pain Volume 36, Number 5, May 2020 www.clinicalpain.com
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the development of OIH. We also assessed the respondent’s
confidence in their ability to diagnose OIH and the degree to
which OIH influences opioid-prescribing decisions. Respond-
ents who endorsed never having encountered OIH in their
practice were only able to complete up to question 10 of the
survey and were not queried about diagnosis, treatment, or
risk factors for OIH. We provided an option for clinicians to
provide written comments regarding OIH.
We pretested the final questionnaire with 5 clinicians
who managed chronic pain patients with opioid therapy
before distribution. The pretest participants were asked to
review the survey to evaluate its clarity and comprehensive-
ness, and the time required for completion. The Hamilton
Integrated Research Ethics Board (HiREB) approved our
survey for dissemination without ethics review.
Questionnaire Administration
An online survey tool (SurveyMonkey Inc., Portland, OR)
was used to facilitate the completion of our questionnaire.
We approached the Canadian Anesthesiologists’Society
(CAS) and the American Society for Regional Anesthesia
and Pain Medicine (ASRA) who identified all of their
members (excluding residents) who reported management
of chronic pain patients. This included 105 CAS members
and 745 ASRA members. In July 2017, representatives from
the CAS and the ASRA sent a link to our online survey via
email to all 850 potential respondents. The survey was made
available for 2 months, and 3 reminder emails were sent at
2-week intervals during the study period. Only clinicians who
endorsed managing chronic pain patients with opioid therapy
were eligible to complete the survey. Respondents were ano-
nymized with the use of a unique identifying number assigned
to each participant.
Data Analysis
We generated frequencies for all collected data and
reported categorical data as proportions. We constructed
univariable and multivariable logistic regression models to
explore the association of country of practice, years in
practice, proportion of practice devoted to chronic pain
management, and proportion of chronic pain patients
receiving long-term opioid therapy with 3 dependent varia-
bles: (1) the degree to which the possibility of OIH influences
the decision to prescribe opioids (“uncertain,”“a little,”and
“not at all”vs. “moderately”and “a lot”); (2) proportion of
physician’s patients with suspected OIH ( ≤5% vs. >5%);
and (3) level of confidence in diagnosing OIH (“not con-
fident”vs. “confident”).
We calculated that we would require at least 90 com-
pleted surveys that endorsed the least common outcome
category for each dependent variable to ensure that our
regression model was reliable (10 respondents for each level
of independent variable considered).13 We presented asso-
ciations in our regression models as odds ratios and 95%
confidence intervals. We assessed goodness-of-fit for our
adjusted regression models with the Hosmer-Lemeshow
(H-L) test. Values of H-L <15.5 indicate a statistically good
fit at the 0.05 level of significance.14 All comparisons were 2
tailed and statistical significance was defined as P-value
≤0.05. All analyses were performed using SPSS Statistics
24.0 (IBM Corp., New York, NY).
Written comments were systematically evaluated by 2
reviewers who developed a coding system to categorize
themes and subthemes. We developed coding rules through
discussion and after 4 rounds of coding written comments,
clusters around themes emerged that we used to build a
coding tree (Appendix 2, Supplemental Digital Content 2,
http://links.lww.com/CJP/A635). Each survey that provided
written comments could contribute >1 theme or subtheme,
but each unique theme or subtheme was only coded once in
a single survey to address the issue of clustering. We applied
our coding strategy, independently and in duplicate, to all
written comments. Disagreements were resolved through
discussion to achieve consensus. We decided, a priori, only
to present subthemes that were endorsed by a minimum of 2
survey respondents. Our selection of illustrative quotes was
guided by consensus among reviewers that selected state-
ments were informative and representative.
RESULTS
The overall response rate for our survey was 37% (318/
850), with response rates of 40% (42/105) and 37% (276/745)
among CAS and ASRA members, respectively. The large
majority of respondents were anesthesiologists (283/318, 89%),
residing in the United States (240/318, 65%), and practicing in
a teaching hospital (215/318, 57%). Most (240/373, 64%) had
been in practice for >10 years and dedicated >40% of their
practice to chronic pain (149/373, 51%) (Table 1).
OIH as a Clinical Entity
Most clinicians (240/318, 76%) reported that at least
some chronic pain patients in their practice had developed
OIH; 19% (61/318) agreed that OIH was a defined clinical
entity but had not witnessed it, 3% (10/318) did not believe
that OIH could occur, and 2% (7/318) had not heard of
OIH. The online survey ended if practitioners reported that
they had not observed OIH in their practice (n =78, 25%),
leaving 240 surveys to inform items pertaining to the
development, diagnosis, and treatment of OIH.
Overall, 23% of respondents (55/240) provided written
comments. Thirteen respondents commented that OIH was
common and of concern to their practice: “[OIH] is a
growing epidemic.”Conversely, 7 written comments sug-
gested that OIH was not clinically important, characterizing
OIH as a “rare and not to be seen phenomenon.”
Influence of OIH on Practice
Practitioners’estimates regarding the occurrence of
OIH among their chronic pain patients varied, but 38% (84/
222) endorsed a prevalence of >5%. Only 19% (41/222)
were very confident in their ability to diagnose OIH; 58%
(129/222) were somewhat confident, and 23% (52/222)
expressed uncertainty or lacked confidence (Table 2). In our
adjusted regression model, >60% of respondent’s chronic
pain patients receiving long-term opioid therapy was asso-
ciated with a higher proportion of patients suspected to have
developed OIH (odds ratio =2.54, 95% confidence interval:
1.24 to 5.18; H-L test =2.68, P=0.95). Our adjusted anal-
ysis did not reveal any factors that were significantly asso-
ciated with confidence in diagnosing OIH (H-L test =4.21,
P=0.84) (Appendix 5, Supplemental Digital Content 5,
http://links.lww.com/CJP/A638). Four characteristics were
endorsed by ≥50% of respondents as important for the
diagnosis of OIH: (1) increasing pain despite opioid dose
escalation (191/222, 86%), (2) increasing demand for
breakthrough opioids (168/222, 76%), (3) diffuse pain (160/
222, 72%), and (4) allodynia (121/222, 55%) (Table 3).
Most respondents (133/222, 60%) reported that OIH
could result from opioid therapy regardless of dose, 22%
(49/222) endorsed that high-dose opioid therapy ( ≥90 mg
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morphine equivalent dose per day) was required, and 18%
(40/222) were uncertain. The degree to which OIH influences
the decision to prescribe opioids varied considerably from
not at all (16/216, 7%), a little (74/216, 34%), moderately
(65/216, 30%), to a lot (41/216, 19%) (Table 2). Our adjusted
analysis did not identify any factors associated with the
consideration of OIH when prescribing opioids (H-L test =
12.83, P=0.12) (Appendix 5, Supplemental Digital Content
5, http://links.lww.com/CJP/A638).
From the free-response analysis, 4 respondents
expressed the view that OIH “remains underdiagnosed and
untreated.”Thirteen respondents commented on challenges
associated with diagnosing OIH: “OIH is difficult to diag-
nose in chronic pain patients because one has to rule out
[competing] conditions. Secondary gain issues need to be
considered too.”Five respondents commented that patients
may resist a diagnosis of OIH: “This condition takes time to
diagnose and to get buy-in from the patient that opioids are
promoting a worsening pain state.”
Risk Factors for OIH
Respondents were divided as to whether certain clinical
conditions or types of opioids were more likely to promote
OIH. Only fibromyalgia (109/216, 51%) and low back pain
TABLE 1. Demographic Characteristics of Survey Responders
Frequency, n (%)
Variables
Respondents
Who Did
Not Observe
OIH in Their
Practice
(N =78)
Respondents
Who
Observed
OIH in Their
Practice
(N =240)
All
Respondents
(N =318)
Age (y)
30-40 18 (23.1) 82 (34.2) 100 (31.4)
41-50 21 (26.9) 52 (21.7) 73 (23.0)
51-60 26 (33.3) 67 (27.9) 93 (29.2)
>60 13 (16.7) 39 (16.3) 52 (16.4)
Sex
Male 60 (76.9) 177 (73.8) 237 (74.5)
Female 18 (23.1) 63 (26.3) 81 (25.5)
Country of practice
Canada 7 (9.0) 35 (14.6) 42 (13.2)
United States 42 (53.8) 164 (68.3) 206 (64.8)
Other 29 (37.2) 41 (17.1) 70 (22.0)
Years in practice
<5 8 (10.3) 45 (18.8) 53 (16.7)
5-10 14 (17.9) 55 (22.9) 69 (21.7)
11-20 22 (28.2) 44 (18.4) 66 (20.7)
21-30 19 (24.4) 59 (24.6) 78 (24.5)
>30 15 (19.2) 37 (15.4) 52 (16.4)
Location of practice
Community
hospital
19 (24.4) 63 (26.3) 82 (25.8)
Teaching hospital 39 (50.0) 141 (58.8) 180 (56.6)
Community clinic 8 (10.3) 32 (13.3) 40 (12.6)
Hospital-based
clinic
11 (14.1) 51 (21.3) 62 (19.5)
Other 11 (14.1) 19 (7.9) 30 (9.4)
Composition of chronic pain patient population
Only chronic
noncancer pain
21 (26.9) 51 (21.3) 72 (22.6)
Only chronic
cancer pain
1 (1.3) 1 (0.4) 2 (0.6)
Both chronic
cancer pain and
noncancer pain
56 (71.8) 188 (78.3) 244 (76.7)
Proportion of practice devoted to chronic pain management
<20% 35 (44.9) 68 (28.3) 103 (32.4)
20%-40% 15 (19.2) 41 (17.1) 56 (17.6)
41%-60% 6 (7.7) 27 (11.3) 33 (10.4)
61%-80% 3 (3.8) 18 (7.5) 21 (6.6)
>80% 19 (24.4) 86 (35.8) 105 (33.0)
Proportion of chronic pain patients receiving long-term opioid
therapy (for cancer or noncancer pain)
<20% 26 (33.3) 71 (29.6) 97 (30.5)
20%-40% 21 (26.9) 56 (23.3) 77 (24.2)
41%-60% 17 (21.8) 59 (24.6) 76 (23.9)
61%-80% 9 (11.5) 33 (13.8) 42 (13.2)
>80% 5 (6.4) 21 (8.8) 26 (8.2)
OIH indicates opioid-induced hyperalgesia.
TABLE 2. Clinical Relevance of OIH Among Chronic Pain Patients
(N =222)
Variables Frequency, n (%)
Degree to which the possibility of OIH influences the decision to
prescribe opioids
A lot 41 (19.0)
Moderately 65 (30.1)
Uncertain 20 (9.3)
A little 74 (34.3)
Not at all 16 (7.4)
Proportion of patients on long-term opioid therapy suspected to
have developed OIH
<0.5% 25 (11.3)
0.5%-1% 32 (14.4)
1.1%-2% 39 (17.6)
2.1%-5% 42 (19.2)
>5% 84 (37.8)
Level of confidence in diagnosing OIH
Very confident 41 (18.5)
Somewhat confident 129 (58.1)
Uncertain 38 (17.1)
Somewhat unconfident 6 (2.7)
Not at all confident 8 (3.6)
OIH indicates opioid-induced hyperalgesia.
TABLE 3. Clinicians’Views Regarding the Clinical Presentation of
Opioid-induced Hyperalgesia (N =222)
Frequency of Presenting Complaint, n (%)
Signs and
Symptoms Never Sometimes Frequently Always
Allodynia 24 (10.8) 77 (34.7) 96 (43.2) 25 (11.3)
Diffuse pain 8 (3.6) 54 (24.3) 117 (52.7) 43 (19.4)
Increasing pain
scores despite
opioid dose
escalation
6 (2.7) 25 (11.3) 94 (42.3) 97 (43.7)
Increasing demand
for breakthrough
opioids
6 (2.7) 48 (21.6) 107 (48.2) 61 (27.5)
Nausea and
vomiting
121 (54.5) 79 (35.6) 17 (7.7) 5 (2.3)
Myoclonus 123 (55.4) 74 (33.3) 21 (9.5) 4 (1.8)
Delirium 122 (55.0) 81 (36.5) 14 (6.3) 5 (2.3)
Unchanged pain
with opioid
rotation
37 (16.7) 90 (40.5) 70 (31.5) 25 (11.3)
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(91/216, 42%) received endorsement by >40% of clinicians,
and 42% (91/216) felt that no single chronic pain condition
was associated with OIH (Appendix 3, Supplemental Digital
Content 3, http://links.lww.com/CJP/A636). Endorsement
for specific types of opioids associated with the development
of OIH ranged from 44% (94/216) for oxycodone to 4%
(8/216) for tramadol, and 27% (59/216) felt that all opioids
posed a similar risk (Appendix 4, Supplemental Digital
Content 4, http://links.lww.com/CJP/A637).
Treatment of OIH
Only 2 approaches for managing OIH were endorsed
by a majority of respondents—reduction of opioid dose
(147/216, 68%) and use of adjunctive medications (133/216, 62%),
although 44% (95/216) endorsed discontinuation of opioids
altogether (Table 4). Three responders provided written
comments that poor awareness of OIH by patients contributed
to challenges with treatment: “Confusing state and frustrating
to diagnose and treat since patients have a hard time
understanding the concept.”Seven respondents wrote that
more education about OIH was needed for clinicians and
patients (Appendix 2, Supplemental Digital Content 2, http://
links.lww.com/CJP/A635).
DISCUSSION
Main Findings
Our survey of chronic pain practitioners found con-
siderable diversity regarding the beliefs and management of
OIH. While most acknowledged OIH as a clinical entity, the
estimated prevalence among chronic pain patients pre-
scribed opioid therapy was variable, and several clinicians
disputed the existence of OIH altogether. However, over a
third of clinicians who perceived OIH in their practice felt it
affected >5% of their chronic pain patients. Respondents
showed little consensus regarding risk factors for the
development of OIH and most only felt somewhat confident
in their ability to diagnose this condition. The overlap
between symptoms of OIH and opioid tolerance was noted
as a complicating factor. Treatment of OIH was also vari-
able, but most clinicians endorsed the reduction of opioid
dose and use of nonopioid adjuvant therapy. Written com-
ments focused on challenges in diagnosing and treating
OIH, the need for more education, and resistance by some
patients to accept this diagnosis.
Findings in Context
Allodynia, diffuse pain, increasing pain scores, and
increasing demand for breakthrough opioids were perceived
to be important clinical indications for OIH, and similar
results were found in a previous survey of pain practitioners.12
Since OIH exacerbates a preexisting pain condition, pain
intensity and opioid consumption would be expected to
increase. Furthermore, OIH may cause diffuse pain and/or
allodynia given that underlying mechanisms involve central
and peripheral sensitization of pronociceptive pathways.1
Most of our respondents did not believe OIH to be limited to
patients receiving high-dose opioids, despite reports in the
literature attributing OIH to high and/or escalating opioid
doses.10,15 A systematic review found evidence that higher
doses of opioid are associated with a reduction of baseline
nociceptive thresholds and increased sensitivity to pain in
response to thermal stimuli; however, there was no association
with opioid dose and response to electrical noxious stimuli.10
Some studies of patients receiving methadone maintenance
therapy for opioid use disorder have failed to show an asso-
ciation between pain tolerance and methadone dose.16,17
Another study has demonstrated biphasic effects of morphine
in a subset of former opioid addicts given morphine.18 As
such, the association between opioid dose and the develop-
ment of OIH remains uncertain.
Many of our respondents endorsed the reduction or
discontinuation of opioids for the treatment of OIH. There is
observational evidence from individuals suspected of OIH
showing a reduction in pain following a 40% to 50% reduction
in their opioid dose.19 An alternative treatment, endorsed by a
third of respondents, was opioid rotation or substitution to a
different opioid, and this approach has also been reported to
reduce symptoms of OIH.1,15,20,21 Rotation to D-methadone
andketaminehasbeenshowntopreventandmediate
symptoms of OIH due to N-methyl-D-aspartate (NMDA)
receptor antagonism.22–26 Switching to dextromethorphan or
α
2
-receptor agonists can have similar effects.1Opioids can
inhibit central nervous glutamate transport, leading to
increased glutamate activation of NMDA receptors.27
Opioid-induced glial activation can also oppose analgesia
through nonstereoselective activation of toll-like receptor 4,
contributing to the release of proinflammatory mediators.28
Treatment of OIH may involve attenuation of mechanisms
that cause pain sensitization through augmented excitatory
response from noxious stimuli. Combining opioid therapy
with a nonopioid adjuvant may also be an effective strategy.
nonsteroidal anti-inflammatory drugs, especially COX-2
inhibitors, reduce the spinal release of excitatory neuro-
transmitters and modulate sensitized NMDA receptors by
blocking prostaglandins.29
A minority of respondents felt that switching from full-
opioid agonists to one with less neurotoxic effects, such as
buprenorphine, may be helpful to treat OIH. Buprenorphine is
a partial opioid agonist and κ-antagonist that is commonly
used to treat opioid dependence in chronic pain patients.30 One
randomized controlled trial31 examined the effects of both
sublingual and intravenous buprenorphine and found that
TABLE 4. Clinicians’Reported Therapeutic Adjustments After
Observing Opioid-induced Hyperalgesia in Practice (N =216)
Treatment
Frequency,
n (%)
Reduction of opioid dose 147 (68.1)
Discontinuation of opioids 95 (44.0)
Initiation of epidural, intrathecal, regional, or local
analgesia (with local anesthetics), and
discontinuation of systemic opioid
79 (36.6)
Switching off the opioid to one with less risk of
neurotoxic effects
80 (37.0)
Switching off the immediate-release opioid to a long-
acting oral opioid
32 (14.8)
Switching off the long-acting oral opioid to an
immediate-release opioid
10 (4.6)
Addition of a nonopioid adjuvant, such as
acetaminophen or a nonsteroidal anti-
inflammatory drug
133 (61.6)
Concomitant administration of oral ketamine,
dextromethorphan, or magnesium (N-methyl-D-
aspartate antagonists)
85 (39.4)
Concomitant administration of intravenous ketamine
and/or dexamethasone
78 (36.1)
Increasing of opioid clearance with the administration
of intravenous fluids
5 (2.3)
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362
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buprenorphine exerted positive antihyperalgesic effects in
human volunteers. Observational studies have also suggested
that switching from high-dose full-opioid agonists to sublingual
buprenorphine in chronic pain patients may result in a mean-
ingfulreductioninpainscores.
32,33 However, other studies have
failed to show that buprenorphine has significant anti-
hyperalgesic effects compared with full opioid agonists.34,35
Half of our respondents endorsed that patients with
fibromyalgia were more susceptible to developing OIH.
Excitatory neurotransmitters contributing to central sensi-
tization are elevated in fibromyalgia and could play a role in
the development of OIH.36 Low back pain was the second
most commonly endorsed condition associated with OIH,
which may reflect that opioids are the most commonly used
class of drugs for the treatment of chronic low back pain in
the United States.37 Our survey did not ask respondents to
distinguish cases of OIH in cancer and noncancer chronic
pain patients. While OIH is primarily attributed to opioid
use for chronic noncancer pain and acute pain, case studies
of patients with terminal cancer have reported exacerbation
of existing pain and/or new diffuse pain in response to
escalating doses of morphine or fentanyl.38–41
Many respondents selected oxycodone, fentanyl, and
morphine as opioids more likely to result in OIH. The
development of OIH has been shown following the use of
potent short-acting µ-opioid agonists such as remifentanil,4
and after potent long-acting µ-opioid agonists such as
morphine.42–44 Systemic or intrathecal administration of
morphine leading to OIH raise the possibility that metab-
olites, such as morphine-3-glucuronide, could contribute to
hyperalgesia.45
Strengths and Limitations
The strengths of our study include a comprehensive
sampling of, largely, anesthesiologists and pain specialists
practicing in North America, who prescribe opioids for
chronic pain. Moreover, our survey development and
administration was consistent with best practices.46 Our
findings are limited by our modest response rate (37%);
however, because we calculated the rate using all possible
respondents as the denominator, and survey completion was
limited to physicians that manage chronic pain with opioids,
our response rate is likely higher. Minimal representation of
primary care providers and clinicians outside of the United
States also reduces the generalizability of our findings.
Implications and Future Research
Chronic pain patients, and their health care providers,
should be aware that opioids may result in OIH and remain
vigilant for this event, particularly if pain increases with
escalating opioid dose. The uncertainty regarding OIH
revealed in our survey highlights the need for standardized
diagnostic criteria and prospective studies to establish the
prevalence of, and risk factors associated with, this disorder
among patients with chronic pain engaged in opioid therapy.
Long-term opioid therapy for chronic noncancer pain is
associated with modest improvements in pain and
function,47,48 andpatientsathighriskofOIHmayoptto
avoid opioids.49 Optimal approaches for treating OIH require
investigation in high-quality randomized controlled trials.
CONCLUSIONS
Most pain practitioners that prescribe opioid therapy
have encountered OIH in their clinical practice, many of
whom expressed concerns that this condition remains
underdiagnosed and undertreated. Clinicians reported vari-
able presentations associated with OIH, highlighting the
need for consensus regarding diagnostic criteria. Further
research is needed to establish the risk of developing OIH
among chronic pain patients, and optimal approaches to
managing this symptom.
ACKNOWLEDGMENTS
The authors thank the American Society for Regional
Anesthesia and Pain Medicine and the Canadian Anesthesi-
ologists’Society for distributing our survey.
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