20150300.0 00030

Anesthesiology, V 122 • No 3 677 March 2015

F OR many decades, physicians have expressed concerns about the manifestation of tolerance to opioids with

long-term use. Tolerance to opioid analgesia can manifest either as loss of pain relief while receiving fixed doses of opi-oids or as the need for dose escalation to maintain the same degree of pain relief. Clinically, such patients end up on high doses of opioid therapy, with persistent high pain intensity, and poor physical and psychosocial function. There are a variety of reasons why relief from pain might be lost (or opi-oid doses escalated) in these patients, including worsening in pain intensity over time, worsening of underlying disease, a desire for hedonistic effects, the emergence of tolerance, or the emergence of opioid-induced hyperalgesia (OIH). OIH is defined as a clinical syndrome in which patients on long-term opioids become more sensitive to pain as a result of taking opioids. Clinically, OIH is characterized by a triad of symptoms: (1) an increase in pain intensity over time, (2) the spreading of pain to other location than the initial painful site, and (3) an increase in pain sensation to external stimuli. Whether clinical OIH truly exists is controversial. OIH has been reliably demonstrated in animal models and there is some clinical evidence to support its occurrence in

humans.1,2 Although opioid tolerance and OIH can be mea-sured in behavioral models in rodents and human experi-mental pain models, the relevance of these models to patients on long-term opioid therapy for chronic pain is unclear.1,3 Recent reviews and meta-analyses have documented remi-fentanil-associated increases in pain, postoperative opioid requirements, and hyperalgesia at or near the surgical site.4 Although the effects of short-acting intraoperative opioids on acute postoperative outcomes is interesting, this topic is

What We Already Know about This Topic

• Opioid-inducedhyperalgesia isaclinicalconceptassociatedwith increasedpainsensitivityanddecreasedefficacyat thesamedoseofopioidswithongoingopioiduse

• Themostappropriatesensorytestingforopioid-inducedhy-peralgesiaisnotclear

What This Article Tells Us That Is New

• Inasystematicreviewof14studiesofopioid-inducedhyper-algesia,mostsensorymodalitiestestedfailedtodemonstratehypersensitivitytoteststimuli,andadditionalworkwithstron-gerstudydesignsisneeded

Copyright © 2014, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. All Rights Reserved. Anesthesiology 2015; 122:677-85

ABSTRACT

Background: Opioid-induced hyperalgesia is a clinical syndrome whereby patients on long-term opioids become more sensi-tive to pain while taking opioids. Opioid-induced hyperalgesia is characterized by increased pain intensity over time, spreading of pain to other locations, and increased pain sensation to external stimuli. To characterize opioid-induced hyperalgesia, labo-ratory methods to measure hyperalgesia have been developed. To determine the performance of these methods, the authors conducted a systematic review of clinical studies that incorporate measures of hyperalgesia in chronic pain patients on long-term opioids.Methods: PubMed and Cochrane databases were searched (terms: opioid induced hyperalgesia, study or trial, and long-term or chronic). Studies published in English were selected if they were conducted in chronic pain patients on long-term opioids and incorporated measures of hyperalgesia; acute/single-dose studies and/or conducted in healthy volunteers were excluded.Results: Fourteen articles made the final selection (11 were selected from the search and 3 others were found from additional sources); there was one randomized controlled trial, one prospective controlled study, three prospective uncontrolled studies, and nine cross-sectional observation studies. Hyperalgesia measurement paradigms used included cold pain, heat pain, pres-sure pain, electrical pain, ischemic pain, and injection pain. Although none of the stimuli were capable of detecting patients’ hyperalgesia, heat pain sensitivity showed some promising results.Conclusions: None of the measures reviewed herein met the criteria of a definitive standard for the measurement of hyper-algesia. Additional studies that use improved study design should be conducted. (Anesthesiology 2015; 122:677-85)

This article is featured in “This Month in Anesthesiology,” page 1A. Submitted for publication June 27, 2014. Accepted for publication October 26, 2014. From the Analgesic Solutions, Natick, Massachusetts

(N.P.K., F.C.P.); and Brigham and Women’s Hospital, Department of Anesthesiology, Perioperative, and Pain Medicine, Harvard Medical School, Chestnut Hill, Massachusetts (R.R.E.).

Review of the Performance of Quantitative Sensory Testing Methods to Detect Hyperalgesia in Chronic Pain Patients on Long-term Opioids

NathanielP.Katz,M.D.,FlorenceC.Paillard,Ph.D.,RobertR.Edwards,Ph.D.

Downloaded From: http://anesthesiology.pubs.asahq.org/pdfaccess.ashx?url=/data/Journals/JASA/932777/ by Samir Sharsharr on 02/25/2015

Anesthesiology 2015; 122:677-85 678 Katz et al.

Measures of Opioid-induced Hyperalgesia in Chronic Pain

beyond the scope of this review which focuses on patients who are maintained on long-term opioid therapy.

To determine whether clinical OIH exists and to char-acterize it, researchers have aimed at developing laboratory methods to measure hyperalgesia (i.e., the increase in pain sen-sitivity, as a proxy to clinical OIH) in chronic pain patients on long-term opioids, outside of the patient’s primary clinical pain syndrome. To this end, laboratory methods have been developed that consist of evaluating patients’ pain thresh-old and tolerance to external experimental stimuli such as mechanical (pressure, touch, or injection), thermal (cold/heat), electrical, or other stimuli (e.g., ischemia). Two pos-sible study designs have been typically used (1) patients with chronic pain on long-term opioids are cross-sectionally com-pared with patients with the same chronic pain syndrome not taking opioids, or (2) patients with chronic pain on long-term opioids are evaluated before and after an interven-tion such as discontinuing opioid therapy. However, none of these experimental approaches have been validated or is con-sidered the definitive standard for measuring hyperalgesia in clinical trials of pain patients on chronic opioids. A suitable method for evaluating hyperalgesia would be reliable and responsive, that is, able to discriminate groups of patients known to have different levels of pain sensitivity that may be associated with opioid therapy. Therefore, we conducted a systematic review of clinical studies that incorporated mea-sures of hyperalgesia in chronic pain patients on long-term opioids to determine and compare the performance of each method to measure hyperalgesia. Because responsiveness requires reliability, we have focused on responsiveness as the key performance characteristic for this review. Finding adequate experimental methods to measure hyperalgesia in chronic pain patients will help determine whether clinical OIH exist, to characterize it, and to prevent or treat it.

Materials and Methods

Literature SearchTo find human studies that measure hyperalgesia in patients on long-term opioids for chronic pain, a search in PubMed and Cochrane databases was performed using terms (“all terms” search) such as “opioid induced hyperalgesia,” “study or trial,” and “long-term or chronic,” and rejecting the terms “mice or rodent.” A first screening of the retrieved articles was performed based on the title and abstract; the screened articles were then retrieved in their full version and carefully read to be included in the final selection. In order for an article to be selected, the study had to meet the following criteria: (1) be a randomized controlled trial, a prospective study, or a cross-sec-tional comparative study; (2) be conducted in patients on long-term opioids for chronic pain (single-dose/acute studies and studies conducted only in healthy volunteers were excluded); (3) include assessments or measures of hyperalgesia as part of the study; and (4) be published in English. The search included articles up to May 2014 (no date limit was used).

The methods used to measure hyperalgesia in the articles retrieved from the main search were compiled. To ensure that all possible original articles were found, a secondary literature search was conducted using the terms “opioid induced hyperalgesia” and the name of the test used to mea-sure hyperalgesia (e.g., cold pressor test, thermal sensory ana-lyzer, lidocaine injection, electrical stimulation, etc.).

Data AnalysisData extracted from the articles included the type of study (studies were categorized into randomized controlled tri-als, prospective controlled studies, prospective uncontrolled studies, and cross-sectional comparative studies), the patient population, the measure(s)/test(s) used to assess hyperalge-sia, available results (difference between pre- and posttreat-ment, difference between groups, dose-related data, and any other relevant data), and P values (when available).

Results

Search ResultsThe article screening and selection process is illustrated in figure 1. The PubMed Library search retrieved 62 articles and the Cochrane database search retrieved 22; a search of our personal records retrieved 1 article. After elimination of duplicates, 68 articles were screened for relevance. A total of 11 articles made the final selection (from most to least recent): Suzan et al.,5 Chu et al.,6 Krishnan et al.,7 Edwards et al.,8 Wang et al.,9 Hooten et al.,10 Chen et al.,11 Ram et al.12 Hay et al.,13 Cohen et al.,14 and Chu et al.15 Search-ing the references of these articles retrieved two other articles (Reznikov et al.16 [cited in Suzan et al.5]; Doverty et al.17 [cited in Chu et al.6]). Another original article was found via the secondary search for OIH and lidocaine injection (Kim et al.18). Thus, a total of 14 original studies that measured hyperalgesia in patients on long-term opioids for chronic pain were found.

Description of StudiesOf the 14 selected studies, 1 was a randomized controlled trial,6 1 was a prospective controlled study,5 3 were prospec-tive uncontrolled studies,9,10,15 and 9 were cross-sectional observation studies.7,8,11–14,16–18 Six hyperalgesia measure-ment paradigms were used in these studies: cold pain, heat pain, pressure pain, electrical pain, ischemic pain, and injec-tion pain; these methods are described in table 1. The design, patient population, and results of each study are summarized in table 2.

Summary of FindingsThe ideal measure would be able to differentiate pain sen-sitivity in patients randomly exposed prospectively to opi-oids compared with a cohort randomly assigned to a control condition. Only one study6 used such a design (randomized controlled trial), and the two experimental methods used in that study (cold pain threshold and tolerance using ice water



PAIN MEDICINE

Fig. 1. Search result flow diagram.

Table 1. Summary of the Methods Used to Measure OIH

Type of Stimulation Test Name Methodology and Measurements References

Cold pain Cold pressor test The subject’s hand is submerged up to the wrist in a 0.5°–1°C ice water bath continuously recirculated by a pump (up to 120 s). Measures are time to pain detection (threshold) and to intolerable pain (withdrawal of the hand; tolerance); continuous pain scores. Painful cold water immer-sion was used as the conditioning stimulus in a CPM paradigm.

Chu et al.,15 Chu et al.,6 Hay et al.,13 Suzan et al.5

Heat pain Medoc TSA (Medoc Ltd. Advanced Med-ical Systems, Ramat Yishai, Israel)

Quantitative pain threshold is determined with the method of limits with the Medoc TSA. A thermode is applied to the skin and heat is applied at various temperatures. Measures are pain threshold and pain tolerance (in °C); pain scores at various temperatures; temporal summation of suprathreshold heat stimuli (in a few studies); ratings of heat pain intensity used as the test stimulus in a CPM paradigm.

Reznikov et al.,16 Chu et al.,15 Chu et al.,6 Suzan et al.,5 Chen et al.,11 Edwards et al.8

Pressure pain

Pressure algom-eter

A manual pressure algometer (e.g., a 3-mm diameter paddle algometer; Medical-Hako, Hamburg, Germany) is pressed perpendicularly to the skin at selected points and increasing pressure is applied. Measures are time to perception of a painful sensation (threshold); the measurement is shown on an algometer scale.

Reznikov et al.16

Electrical pain

Electrical stimula-tion of ear lobe

Voltage is applied to ear lobe starting at 0 V and increasing at a constant rate of 2 V every 1.4 s, up to a maximum of 100 V. Measures are pain threshold and pain tolerance (in volts).

Doverty et al.,17 Krishnan et al.,7 Hay et al.13

Ischemic pain

Blood pres-sure cuff test with handgrip exercise

A blood pressure cuff is placed around the nondominant arm of the subject and the pressure is increased to 20 mmHg above the subject’s systolic pressure. With the pressure maintained, subjects perform a handgrip exercise on an elastic ball, in accordance with the rhythm of a metro-nome (subject’s eyes are covered to minimize distraction and time cues). Measures are time to feeling of pain (pain threshold); time to untolerable pain (to a maximum of 5 min) (pain tolerance).

Krishnan et al.,7 Ram et al.12

Injection pain

Subcutaneous local anes-thetic injection

A local anesthetic (generally lidocaine) is administered subcutaneously (before a full dose of anesthetic for a procedure). Measures are subject’s ratings of pain and unpleasantness of the lidocaine injection.

Cohen et al.14

CPM = conditioned pain modulation; OIH = opioid-induced hyperalgesia; TSA = thermal sensory analyzer.




Tab

le 2

. S

umm

ary

of S

tud

ies

on O

IH in

Pat

ient

s Ta

king

Lon

g-te

rm O

pio

ids

Exp

erim

enta

l P

ain

Par

adig

mTe

st N

ame*

Pat

ient

Pop

ulat

ion

Res

ults

Ref

eren

ce

RC

Ts

Col

d p

ain

H

eat

pai

nC

old

pre

ssor

tes

tTh

erm

al S

enso

ry a

na-

lyze

r (M

edoc

Med

oc

Ltd

. Ad

vanc

ed M

edic

al

Sys

tem

s, R

amat

Yis

hai,

Isra

el)

Pat

ient

s w

ith L

BP

tre

ated

with

sus

-ta

ined

-rel

ease

mor

phi

ne (n

= 6

9) o

r p

lace

bo

(n =

70)

for

1 m

o. P

atie

nts

sub

ject

ed t

o a

targ

et-c

ontr

olle

d

infu

sion

with

the

op

ioid

ago

nist

re

mife

ntan

il or

sal

ine.

Col

d p

ain:

Pat

ient

s in

the

mor

phi

ne g

roup

had

sig

nific

ant

chan

ges

in p

ain

thre

sh-

old

from

bas

elin

e (P

= 0

.005

). Th

ere

wer

e no

sig

nific

ant

chan

ges

from

bas

elin

e in

to

lera

nce

in b

oth

grou

ps.

The

re w

ere

no s

igni

fican

t d

iffer

ence

s in

the

cha

nges

for

thre

shol

d a

nd t

oler

ance

bet

wee

n th

e tw

o gr

oup

s.H

eat

pai

n: P

atie

nts

in e

ach

trea

tmen

t gr

oup

had

sig

nific

ant

chan

ges

in p

ain

thre

sh-

old

from

bas

elin

e (P

= 0

.05

for

mor

phi

ne g

roup

; P =

0.0

06 fo

r p

lace

bo

grou

p).

Ther

e w

ere

no s

igni

fican

t ch

ange

s fr

om b

asel

ine

in t

oler

ance

in b

oth

grou

ps.

Th

ere

wer

e no

sig

nific

ant

diff

eren

ces

in t

he c

hang

es in

pai

n th

resh

old

and

tol

er-

ance

bet

wee

n gr

oup

s.

Chu

et

al.6

Pro

spec

tive

co

ntro

lled

(no

nran

do

miz

ed) s

tud

ies

H

eat

pai

n in

tens

ity

Col

d p

ain

Ther

mal

Sen

sory

Ana

lyze

r (M

edoc

)C

old

pre

ssor

tes

t

Pat

ient

s (n

= 3

0) w

ith c

hron

ic n

eu-

rop

athi

c (r

adic

ular

) pai

n as

sess

ed

bef

ore

and

aft

er 4

wk

of a

n in

di-

vid

ually

titr

ated

dos

e of

ora

l HM

(4

–20

mg/

d).

Hea

lthy

volu

ntee

rs

(n =

10)

use

d a

s co

ntro

l (re

ceiv

e no

op

ioid

s).

Hea

t p

ain:

HM

tre

atm

ent

resu

lted

in a

sig

nific

ant

rise

for

the

entir

e gr

oup

, on

aver

age,

in t

he in

tens

ity o

f the

pha

sic

heat

pai

n re

spon

se (V

AS

at

bas

e-lin

e =

48.

2 ±

33.

1; a

t w

k 4

= 6

0.8

± 2

9; P

< 0

.05)

. No

sign

ifica

nt d

iffer

ence

s fo

r co

ntro

ls in

the

inte

nsity

of t

he p

hasi

c he

at p

ain

resp

onse

bet

wee

n b

asel

ine

and

w

k 4

(32.

9 ±

27

vs. 3

3.9

± 2

8, r

esp

ectiv

ely;

P =

0.6

5).

Col

d p

ain:

No

sign

ifica

nt d

iffer

ence

s in

col

d p

ain

tole

ranc

e b

etw

een

bas

elin

e an

d

wk

4 fo

r H

M p

atie

nts

(40.

1 ±

41.

6 vs

. 43.

9 ±

48.

8; P

= 0

.38)

or

cont

rols

(27.

9 ±

15.

8 vs

. 30

± 1

9.5;

P =

0.4

4).

Suz

an

et a

l.5

Pro

spec

tive

unc

ont

rolle

d s

tud

ies

(fro

m m

ost

to

less

rec

ent)

H

eat/

cold

p

ain

Ther

mal

Sen

sory

Ana

lyze

r (M

edoc

)P

atie

nts

with

LB

P t

akin

g op

ioid

s (n

= 3

5) b

eing

tap

ered

off;

pat

ient

s w

ith L

BP

not

tak

ing

opio

ids

(n =

35)

; hea

lthy

cont

rols

(n =

28)

Par

amet

ers

mea

sure

d: c

old

and

hea

t p

ain

thre

shol

d in

low

bac

k an

d n

ond

omi-

nant

han

d b

efor

e (T

1), a

nd 3

wk

(T2)

and

6 m

o p

osto

pio

id t

aper

ing

(T3)

. Op

ioid

p

atie

nts

wer

e of

f op

ioid

s b

y T2

and

rem

aine

d o

ff at

T3.

Hea

t p

ain

thre

shol

ds:

Op

ioid

pat

ient

s ha

d lo

wer

hea

t p

ain

thre

shol

ds

than

con

-tr

ols

at a

ll tim

e p

oint

s (T

1, P

= 0

.007

; T2,

P =

0.0

07; T

3, P

= 0

.017

). N

onop

ioid

p

atie

nts

had

low

er h

eat

pai

n th

resh

old

tha

n co

ntro

ls a

t T1

(P =

0.0

01) a

nd T

2 (0

.002

). A

t T3

, hea

t p

ain

thre

shol

ds

of n

onop

ioid

pat

ient

s no

rmal

ized

. The

re w

as

no d

iffer

ence

bet

wee

n op

ioid

and

non

opio

id p

atie

nts

at a

ny t

ime

poi

nt.

Col

d p

ain

thre

shol

ds:

Op

ioid

pat

ient

s ha

d lo

wer

thr

esho

ld t

o co

ld s

timul

i tha

n no

nop

ioid

pat

ient

s (P

= 0

.004

for

hand

) and

con

trol

s (P

= 0

.001

for

hand

, P

= 0

.021

for

left

low

bac

k). N

onop

ioid

pat

ient

s ha

d a

col

d p

ain

thre

shol

d s

imila

r to

con

trol

s.

Wan

g et

al.9

H

eat

pai

nS

tand

ard

ized

QS

T: a

uto-

mat

ed C

omp

uter

Aid

ed

Sen

sory

Eva

luat

or IV

Pat

ient

s (n

= 1

09) t

akin

g op

ioid

s ad

mitt

ed t

o a

mul

tidis

cip

linar

y p

ain

reha

bili

tatio

n p

rogr

am w

hich

in

clud

es o

pio

id t

aper

ing

over

3 w

k.

(QS

T p

erfo

rmed

bef

ore

and

aft

er

tap

er).

Gre

ater

bas

elin

e m

orp

hine

dos

e w

as a

ssoc

iate

d w

ith lo

wer

or

mor

e hy

per

alge

sic

valu

es o

f HP

5-0

.5†

(P =

0.0

40).

Tap

erin

g of

gre

ater

mor

phi

ne d

oses

was

ass

oci-

ated

with

low

er v

alue

s of

HP

5-0

.5†

(P =

0.0

01).

Hoo

ten

et a

l.10

C

old

pai

n

Hea

t p

ain

Col

d p

ress

or t

est

Ther

mal

Sen

sory

Ana

lyze

r (M

edoc

)

Pat

ient

s (n

= 6

) with

LB

P t

akin

g m

or-

phi

ne a

sses

sed

bef

ore

and

1 m

o af

ter

trea

tmen

t.

Col

d p

ain:

Pat

ient

s d

evel

oped

sig

nific

ant

hyp

eral

gesi

a to

col

d p

ress

or p

ain

afte

r 1

mo

of o

ral m

orp

hine

the

rap

y (P

< 0

.01)

. Pai

n th

resh

old

dro

pp

ed b

y ap

pro

xi-

mat

ely

16%

(fro

m 1

2.1

± 4

.1 t

o 10

.1 ±

3.7

s),

and

pai

n to

lera

nce

dro

pp

ed b

y ap

pro

xim

atel

y 24

% (f

rom

28.

0 ±

13.

7 to

19.

8 ±

6.0

s).

Hea

t p

ain:

Hea

t p

ain

thre

shol

d d

id n

ot c

hang

e si

gnifi

cant

ly b

etw

een

sess

ions

(−

0.2°

± 0

.6°C

).

Chu

et

al.15

(Con

tinue

d)



PAIN MEDICINE

Cro

ss-s

ecti

ona

l co

mp

arat

ive

stud

ies

(fro

m m

ost

to

less

rec

ent)

In

ject

ion

Sub

cuta

neou

s in

ject

ion

of L

AP

atie

nts

taki

ng o

pio

ids

(n =

62)

; p

atie

nts

not

taki

ng o

pio

ids

(n =

20)

.LA

inje

ctio

n-sp

ecifi

c p

ain

scor

e, u

nple

asan

tnes

s, a

nd b

ehav

ior

pai

n sc

ore

are

high

er in

op

ioid

pat

ient

s (a

t an

y d

ose)

vs.

non

opio

id p

atie

nts

(P <

0.0

1). I

n no

no-

pio

id p

atie

nts,

pos

tinje

ctio

n p

ain

scor

es, u

nple

asan

tene

ss, a

nd b

ehav

iora

l pai

n sc

ore

wer

e hi

gher

in p

atie

nts

taki

ng h

igh

dos

e (≥

200

mg)

tha

n th

ose

taki

ng lo

w

dos

es (1

–59

mg)

(P <

0.0

5).

Kim

et

al.18

C

old

pai

n

Ele

ctric

al

pai

n

Mec

hani

-ca

l pai

n

Isch

emic

p

ain

Col

d p

ress

or t

est

Ele

ctric

al s

timul

atio

n of

ear

lo

be

Pre

ssur

e al

gom

eter

Blo

od p

ress

ure

cuff

and

ha

ndgr

ip e

xerc

ise

Op

ioid

-dep

end

ent

sub

ject

s (n

= 1

6)

on M

eth

or B

up (n

= 8

eac

h);

heal

thy

cont

rols

(n =

16)

.

Col

d p

ain:

The

re w

ere

sign

ifica

nt t

reat

men

t gr

oup

diff

eren

ces

in c

old

pai

n th

resh

old

an

d t

oler

ance

, with

the

op

ioid

gro

ups

bei

ng m

ore

sens

itive

tha

n co

ntro

ls. H

azar

d

ratio

for

pai

n th

resh

old

was

6.8

(95%

CI,

2.2–

20.6

) in

Bup

gro

up a

nd 4

.1 (9

5%

CI,

1.4–

11.7

) in

Met

h gr

oup

vs.

con

trol

s. H

azar

d r

atio

for

tole

ranc

e w

as 7

.7 (9

5%

CI,

2.6–

23.3

) in

Bup

gro

up a

nd 4

.5 (9

5% C

I, 1.

7–15

.6) i

n M

eth

grou

p v

s. c

ontr

ols.

Ele

ctric

pai

n: T

here

wer

e si

gnifi

cant

tre

atm

ent

grou

p d

iffer

ence

s in

ele

ctric

al

thre

shol

d b

ut n

ot t

oler

ance

, with

hig

her

thre

shol

ds

in t

he o

pio

id g

roup

s. F

or

thre

shol

d, g

eom

etric

mea

n w

as 1

.5-f

old

(95%

CI,

1.1–

1.9)

tha

n th

at o

f con

trol

in

the

Bup

gro

up a

nd 1

.3-f

old

(95%

CI,

1.04

–1.7

) tha

t th

at o

f con

trol

in M

eth

grou

p.

Isch

emic

and

pre

ssur

e p

ain:

No

sign

ifica

nt d

iffer

ence

s b

etw

een

trea

tmen

t gr

oup

s fo

r ei

ther

thr

esho

ld o

r to

lera

nce

for

isch

emic

and

pre

ssur

e p

ain

test

s.

Kris

hnan

et

al.7

M

echa

ni-

cal p

ain

P

ress

ure

pai

n

Hea

t p

ain

Pun

ctat

e m

echa

nica

l p

rob

es—

mec

hani

cal

tem

por

al s

umm

atio

nP

ress

ure

pro

be

Ther

mal

Sen

sory

Ana

lyze

r (M

edoc

)

Chr

onic

pai

n p

atie

nts

with

sp

inal

pai

n ta

king

low

-dos

e op

ioid

s (n

= 8

8);

high

-dos

e op

ioid

s (n

= 9

1); o

r no

op

ioid

s (n

= 9

7).

Mec

hani

cal p

ain:

No

sign

ifica

nt d

iffer

ence

s b

etw

een

grou

ps

in m

echa

nica

l pai

n se

nsiti

vity

.P

ress

ure

pain

: No

sign

ifica

nt d

iffer

ence

s be

twee

n gr

oups

in p

ress

ure

pain

sen

sitiv

ity.

Hea

t p

ain:

No

sign

ifica

nt d

iffer

ence

s b

etw

een

grou

ps

in (c

old

/war

m) t

herm

al s

en-

sitiv

ity.

Ed

war

ds

et a

l.8

H

eat

pai

n

Mec

hani

-ca

l pai

n

Ther

mal

Sen

sory

Ana

lyze

r (M

edoc

)Vo

n Fr

ey fi

lam

ents

Pin

pric

k

Chr

onic

pai

n p

atie

nts

taki

ng o

pio

ids

(n =

58)

; chr

onic

pai

n p

atie

nts

not

taki

ng o

pio

ids

(n =

41)

; con

trol

s:

heal

thy

volu

ntee

rs n

ot t

akin

g op

i-oi

ds

(n =

41)

.

Hea

t p

ain:

Sta

tistic

ally

sig

nific

ant

diff

eren

ces

wer

e d

etec

ted

am

ong

thre

e gr

oup

s in

he

at p

ain

thre

shol

d (P

= 0

.02)

, col

d p

ain

tole

ranc

e (P

= 0

.01)

, hea

t p

ain

tole

r-an

ce (P

= 0

.01)

, and

dur

atio

n of

tol

eran

ce t

o th

e su

pra

thre

shol

d h

eat

stim

ulat

ion

(P =

0.0

2). P

ost

hoc

anal

ysis

sho

wed

sig

nific

ant

diff

eren

ces

in t

hese

four

par

am-

eter

s b

etw

een

opio

id p

atie

nts

and

con

trol

s (P

< 0

.05)

but

not

bet

wee

n no

nop

ioid

p

atie

nts

and

con

trol

s. T

he d

egre

e of

tem

por

al s

umm

atio

n of

the

sec

ond

pai

n w

as s

igni

fican

tly e

xace

rbat

ed in

op

ioid

pat

ient

s vs

. non

opio

id p

atie

nts

and

con

-tr

ols

(P <

0.0

5) (n

o d

iffer

ence

s b

etw

een

nono

pio

id p

atie

nts

and

con

trol

s). O

pio

id

dos

e co

rrel

ated

(mor

phi

ne e

qui

vale

nt ≥

75 m

g) w

ith t

he d

ecre

ased

hea

t p

ain

thre

shol

d a

nd e

xace

rbat

ed t

emp

oral

sum

mat

ion

of t

he s

econ

d p

ain

in o

pio

id

pat

ient

s (P

< 0

.05)

.M

echa

nica

l pai

n: N

o d

iffer

ence

s b

etw

een

grou

ps

in m

echa

nica

l pai

n th

resh

old

fr

om v

on F

rey

filam

ents

and

pin

pric

k.

Che

n et

al.11

C

old

pai

n

CP

MC

old

pre

ssor

tes

tH

eat

stim

ulat

ion

(Med

oc)

+ c

old

stim

ulat

ion

(col

d

pre

ssor

tes

t)

Chr

onic

pai

n p

atie

nts

on o

pio

ids

(n =

73)

; chr

onic

pai

n p

atie

nts

not

on o

pio

ids

(n =

37)

.

Col

d p

ain:

No

sign

ifica

nt d

iffer

ence

s b

etw

een

grou

ps.

CP

M: T

he m

agni

tud

e of

CP

M w

as s

igni

fican

tly la

rger

in t

he n

onop

ioid

gro

up t

han

in t

he o

pio

id g

roup

(P =

0.0

03).

Ram

et

al.12

Tab

le 2

. C

ontin

ued

Exp

erim

enta

l P

ain

Par

adig

mTe

st N

ame*

Pat

ient

Pop

ulat

ion

Res

ults

Ref

eren

ce

(Con

tinue

d)




M

echa

ni-

cal p

ain

C

old

pai

n

Ele

ctric

al

pai

n

Von

Frey

fila

men

tsC

old

pre

ssor

tes

tE

lect

rical

stim

ulat

ion

Chr

onic

pai

n p

atie

nts

taki

ng m

or-

phi

ne o

r m

etha

don

e m

ore

than

on

ce d

aily

for

≥1 m

o; M

eth-

mai

n-ta

ined

pat

ient

s re

crui

ted

from

a

met

had

one

mai

nten

ance

pro

gram

; co

ntro

ls: o

pio

id-n

aive

sub

ject

s.

N =

10

in e

ach

grou

p.

Mec

hani

cal p

ain:

The

re w

ere

no s

igni

fican

t diff

eren

ces

in K

apla

n–M

eier

cur

ves

for

each

of t

he g

roup

for v

on F

rey

hair

pain

thre

shol

d (P

= 0

.33)

or t

oler

ance

(P =

0.9

9).

Col

d p

ain:

Tol

eran

ce v

alue

s (m

ean

± S

EM

) wer

e 18

.1 ±

2.6

s in

mor

phi

ne p

atie

nts,

19

.7 ±

2.3

s in

Met

h p

atie

nts,

and

18.

9 ±

1.9

s in

Met

h-m

aint

aine

d p

atie

nts;

all

valu

es a

re s

igni

fican

tly (P

< 0

.05)

low

er t

han

opio

id-n

aive

sub

ject

s (3

0.7

± 3

.9 s

). Th

resh

old

val

ues

wer

e no

t d

iffer

ent

bet

wee

n gr

oup

s.E

lect

rical

pai

n: E

lect

rical

thr

esho

ld a

nd t

oler

ance

val

ues

wer

e no

t si

gnifi

cant

ly d

if-fe

rent

bet

wee

n gr

oup

s.

Hay

et

al.13

In

ject

ion

Sub

cuta

neou

s in

ject

ion

of

loca

l ane

sthe

ticP

atie

nts

(n =

355

) on

stea

dy

regi

men

of

op

ioid

s (d

oses

1 t

o >

300

mg)

an

d s

ched

uled

for

an in

terv

entio

nal

pro

ced

ure.

Con

trol

s: h

ealth

y vo

lunt

eers

(n =

27)

no

t ta

king

op

ioid

s.

Op

ioid

dos

e p

ositi

vely

cor

rela

ted

with

pai

n in

tens

ity (P

< 0

.05

at a

ll d

oses

[whi

ch

star

t at

1 m

g] v

s. n

o op

ioid

s) a

nd u

nple

asan

tene

ss s

core

(P <

0.0

5 fo

r d

oses

≥3

0 m

g on

ly v

s. n

o op

ioid

s). D

urat

ion

of o

pio

id t

reat

men

t w

as p

ositi

vely

cor

re-

late

d w

ith b

oth

pai

n an

d u

nple

asan

tnes

s sc

ores

(P =

0.0

01 v

s. d

urat

ion

= 0

).

Coh

en

et a

l.14

M

echa

ni-

cal p

ain

P

ress

ure

pai

n

Hea

t p

ain

Von

Frey

fila

men

tsM

anua

l alg

omet

erTh

erm

al S

enso

ry A

naly

zer

(Med

oc)

Op

ioid

-tre

ated

pat

ient

s (n

= 1

42);

nono

pio

id-t

reat

ed g

roup

(n =

82)

Mec

hani

cal p

ain:

No

sign

ifica

nt d

iffer

ence

s b

etw

een

grou

ps

wer

e fo

und

for

mec

hani

cal p

ain

(diff

eren

ce =

17.

0 g

[95%

CI,

8.8–

42.8

], P

= 0

.19)

.P

ress

ure

pai

n: N

o d

iffer

ence

bet

wee

n gr

oup

s w

ere

foun

d fo

r p

ress

ure

pai

n (2

.2

mm

Hg

[28.

7–33

.2],

P =

0.8

9)H

eat

pai

n: N

o d

iffer

ence

bet

wee

n gr

oup

s w

ere

foun

d fo

r he

at p

ain

thre

shol

d

(−0.

3°C

[−1.

5 to

0.9

], P

= 0

.70)

or

sup

rath

resh

old

hea

t p

ain

inte

nsity

(diff

eren

ce

bet

wee

n m

axim

al p

ain

inte

nsiti

es =

−0.

4 N

PS

uni

ts [1

.2, 0

.4],

P =

0.3

1).

Rez

niko

v et

al.16

C

old

pai

n

Ele

ctric

p

ain

Col

d p

ress

or t

est

Ele

ctric

al s

timul

atio

n of

ear

lo

be

Pat

ient

s (n

= 1

6) o

n st

able

, onc

e-d

aily

d

oses

of m

etha

don

e an

d m

atch

ed

cont

rol s

ubje

cts

(n =

16)

.

Col

d p

ain:

Met

h p

atie

nts

det

ecte

d p

ain

sign

ifica

ntly

ear

lier

than

con

trol

s at

0 h

and

w

ere

also

muc

h le

ss p

ain

tole

rant

tha

n co

ntro

ls a

t 0

and

3 h

. No

sign

ifica

nt d

iffer

-en

ces

in p

ain

det

ectio

n va

lues

bet

wee

n gr

oup

s at

3 h

. Pai

n to

lera

nce/

pai

n d

etec

-tio

n ra

tios

for

Met

h p

atie

nts

wer

e si

gnifi

cant

ly lo

wer

tha

n co

ntro

ls a

t 0

and

3 h

.E

lect

rical

pai

n: M

eth

pat

ient

s’ p

ain

tole

ranc

e va

lues

wer

e lo

wer

tha

n co

ntro

ls a

t 0

h, b

ut h

ighe

r th

an c

ontr

ols

at 3

h; n

o si

gnifi

cant

diff

eren

ces

in p

ain

det

ectio

n va

lues

wer

e fo

und

. Pai

n to

lera

nce/

pai

n d

etec

tion

ratio

s fo

r M

eth

pat

ient

s w

ere

sign

ifica

ntly

low

er t

han

cont

rols

at

0 h

only

.

Dov

erty

et

al.17

* R

efer

to

tab

le 1

for

tes

t d

escr

iptio

n. †

Mea

sure

men

ts a

re b

ased

on

the

met

hod

of

leve

ls. H

eat

pai

n p

erce

ptio

n (H

P 5

, HP

0.5

, and

HP

5-0

.5) a

re c

alcu

late

d. H

P 0

.5 is

the

mid

poi

nt b

etw

een

a no

npai

nful

stim

ulus

an

d t

he le

ast

stim

ulus

mag

nitu

de

nece

ssar

y to

elic

it p

ain;

thu

s, H

P 0

.5 is

a m

easu

re o

f HP

thr

esho

ld. H

P 5

is t

he s

timul

us m

agni

tud

e ne

cess

ary

to e

licit

a p

ain

ratin

g of

5 fr

om t

he s

ubje

ct; t

hus,

HP

5 is

con

sid

ered

to

be

a m

easu

re o

f int

erm

edia

tely

inte

nse

pai

n. H

P 5

-0.5

is a

mea

sure

of t

he s

lop

e of

the

line

con

nect

ing

thes

e tw

o p

oint

s, a

nd t

his

HP

par

amet

er h

as b

een

term

ed t

he p

ain-

stim

ulus

res

pon

se s

lop

e.B

up =

bup

reno

rphi

ne; C

PM

= c

ond

ition

ed p

ain

mod

ulat

ion;

HM

= h

ydro

mor

pho

ne; H

P =

hea

t pai

n p

erce

ptio

n; L

A =

loca

l ane

sthe

tic; L

BP

= lo

w b

ack

pai

n; M

eth

= m

etha

don

e; N

PS

= n

umer

ical

pai

n sc

ale;

OIH

= o

pi-

oid

-ind

uced

hyp

eral

gesi

a; Q

ST

= q

uant

itativ

e se

nsor

y te

stin

g; R

CT

= r

and

omiz

ed c

ontr

olle

d t

rial;

VAS

= v

isua

l ana

log

scal

e.

Tab

le 2

. C

ontin

ued

Exp

erim

enta

l P

ain

Par

adig

mTe

st N

ame*

Pat

ient

Pop

ulat

ion

Res

ults

Ref

eren

ce



PAIN MEDICINE

Tab

le 3

. S

umm

ary

of R

esul

ts*

from

the

Sel

ecte

d S

tud

ies

Diff

eren

ces

M

easu

red

*

Col

d

Pre

ssor

To

lera

nce

Col

d

Pre

ssor

Th

resh

old

Hea

t

Pai

n

Tole

ranc

e

Hea

t P

ain

Thre

shol

d (a

nd

Sup

rath

resh

old

)

Hea

t

Pai

n

Inte

nsity

Hea

t P

ain

C

PM

Ele

ctric

al

Pai

nIn

ject

ion

P

ain

Mec

hani

cal†

Isch

emic

or

Oth

er

Pre

ssur

e

Pai

n

RC

Ts

Chu

et

al. 6

Bet

wee

n gr

oup

−−

−−

Pre

–pos

t−

+−

+

Pro

spec

tive

co

ntro

lled

stu

die

s (n

onr

and

om

ized

)

Suz

an e

t al

.5B

etw

een

grou

p−

+P

re–p

ost

−+

Pro

spec

tive

unc

ont

rolle

d s

tud

ies

W

ang

et a

l.9B

etw

een

grou

p−

Pre

–pos

t−

H

oote

n et

al.10

Pre

–pos

t+

C

hu e

t al

.15P

re–p

ost

++

−

Cro

ss-s

ecti

ona

l co

mp

arat

ive

stud

ies

K

im e

t al

.18B

etw

een

grou

p+

K

rishn

an e

t al

. 7B

etw

een

grou

p+

+±

−−

H

ay e

t al

.13B

etw

een

grou

p+

−−

−

Ed

war

ds

et a

l.8B

etw

een

grou

p−

−−

−

Che

n et

al.11

Bet

wee

n gr

oup

++

−

Ram

et

al.12

Bet

wee

n gr

oup

−−

+

Coh

en e

t al

.14B

etw

een

grou

p+

R

ezni

kov

et a

l.16B

etw

een

grou

p−

−−

D

over

ty e

t al

.17B

etw

een

grou

p±

±−

Num

ber

of

po

siti

ve s

tud

ies

33

12

31

02

00

Num

ber

of

neg

ativ

e st

udie

s5

32

62

02

05

2

* +

ind

icat

es a

pos

itive

find

ing;

− in

dic

ates

a n

egat

ive

find

ing.

± in

dic

ates

an

equi

voca

l find

ing

(stu

die

s w

ith ±

find

ings

are

not

tak

en in

to a

ccou

nt in

the

tot

al o

f ne

gativ

e an

d p

ositi

ve s

tud

ies)

. Fo

r p

re–p

ost

com

-p

aris

ons,

a “

+”

ind

icat

es t

hat

pat

ient

s on

op

ioid

s ar

e m

ore

sens

itive

to

pai

n af

ter

long

-ter

m o

pio

id t

reat

men

t, a

s as

sess

ed b

y th

e te

st (o

r th

at t

aper

ing

of o

pio

id s

igni

fican

tly d

ecre

ases

pai

n se

nsiti

vity

). Fo

r gr

oup

co

mp

aris

ons,

a “

+”

ind

icat

es t

hat

pat

ient

s on

op

ioid

s ar

e m

ore

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immersion and heat pain threshold and tolerance using the Medoc TSA; Medoc Ltd. Advanced Medical Systems, Ramat Yishai, Israel) both failed to differentiate the two groups. It is unclear whether these approaches failed because of the measures, because the patients did not in fact develop hyper-algesia, or because treatment was short term and used rela-tively low doses. Thus, no measure of hyperalgesia can claim definitive standard status.

Table 3 summarizes the test results by indicating which measures were used in each study, and whether the P value for the between-group difference tested was greater than 0.05 (−) or less than 0.05 (+). The major methods that have been used are (1) cold pain threshold and tolerance using ice water immersion, and (2) heat pain threshold, tolerance, or intensity at suprathreshold stimulus levels using computer-controlled thermode devices. The summary results in table 3 suggest that, on average, none of the stimuli were capable of detecting hyperalgesia in chronic pain patients on long-term opioids. However, some specific findings merit attention. For instance, two controlled prospective studies5,6 and one uncontrolled prospective study10 found a significant differ-ence in heat pain sensitivity between pre- and postopioid treatment.

DiscussionThis systematic review was conducted to determine and compare the responsiveness of methods to measure hyperal-gesia in clinical studies of chronic pain patients on long-term opioids. Fourteen articles reporting original studies measur-ing hyperalgesia in those patients were retrieved. Because clinical OIH has not yet been definitively demonstrated, it is not possible to directly determine the responsiveness of measures of this phenomenon. Furthermore, the stud-ies performed in this area tend to have small sample sizes, different experimental designs, and different testing proto-cols, thereby precluding formal meta-analytic methods. The summary results in table 3 suggest that, on average, none of the stimuli have sufficient power to detect hyperalgesia in chronic pain patients on long-term opioids. However, some specific findings merit attention. For instance, it is notable that three prospective studies that assessed heat pain ratings reported heat hyperalgesia when patients were on opioid therapy (compared with when they were off opioids).5,6,10 Although a larger number of studies have been performed with ice water immersion, a substantial proportion of these studies failed to discriminate “known” groups, and the aver-sive nature of the test should be considered. Mechanical testing approaches (algometry or von Frey filaments) have been used several times, never successfully.7,8,11,13,16 Other approaches (conditioned pain modulation, ischemia, injec-tion pain) have been unsuccessful, inconsistent, or have been used too rarely to conclude.7,8,12,14,18

Thus, this review failed to identify a definitive standard for hyperalgesia measures. This is mainly due to the fact that the measurements failed to detect a change because the

measures are not sensitive enough, the sample is too small for the measure to detect change, the studies use subopti-mal study designs (most being cross-sectional), and/or the timing of opioid dosing was not controlled for. Moreover, all these studies provide averages of hyperalgesia variables over the entire group of opioid-treated patients, which may obliterate the phenomenon if the development of hyperal-gesia is a rare occurrence in patients on opioids. Therefore, clinicians who wish to conduct a clinical trial to measure hyperalgesia in opioid-treated patients should choose a randomized controlled trial design and report the propor-tion of patients on opioids who develop hyperalgesia dur-ing the treatment. Finally, although most studies focused on measure responsiveness, assessing reliability and other forms of validity would also be informative. This review identified heat stimuli (using the Medoc TSA; Medoc Ltd. Advanced Medical Systems) as a potentially good candidate for further testing in future studies. More data should also be generated with injection pain to determine whether this method holds true potential.

Importantly, clinicians should be cautious not to take the increase in pain sensitivity (hyperalgesia) to experimental stimuli as a proof of OIH in opioid-treated patients. Indeed, clinical OIH is a syndrome that has three main symptoms: one of them being an increase in pain sensitivity to external stimuli and the other two being an increase in pain inten-sity over time and the spreading of pain to other locations. To conclude that a patient experiences OIH should rely on additional evaluation of the patient’s clinical data and medi-cal history to determine whether all characteristics of clinical OIH are present. To this end, Chen et al.11 provides a list of clinical factors that should be taken into account in the diagnosis of clinical OIH.

AcknowledgmentsThis study was funded by Campbell Alliance, Raleigh, North Carolina.

Competing InterestsThe authors declare no competing interests.

CorrespondenceAddress correspondence to Dr. Paillard: Analgesic Solutions, 232 Pond Street, Natick, Massachusetts 01760. fpaillard@ analgesicsolutions.com. This article may be accessed for personal use at no charge through the Journal Web site, www.anesthesiology.org.

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