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OPIOIDS, SUBSTANCE ABUSE &ADDICTIONS SECTION

Original Research Article

Longitudinal Observation of Changes in PainSensitivity during Opioid Tapering in Patientswith Chronic Low-Back Painpme_1276 1720..1726

Haili Wang, MD, Michael Akbar, MD,

Nina Weinsheimer, MD, Simone Gantz, Dipl-SozWiss, and Marcus Schiltenwolf, MD

Department of Orthopedics, Trauma Surgery and

Paraplegiology, University Hospital of Heidelberg,

Heidelberg, Germany

Reprint requests to: Haili Wang, MD, Division of PainManagement, Department of Orthopedic Surgery,University of Heidelberg, Schlierbacher Landstrasse200a, 69118 Heidelberg, Germany. Tel:+49-6221-966505; Fax: +49-6221-966230; E-mail:[email protected].

There are no financial or other relationships that mightlead to a conflict of interest.

The first two authors contributed equally to thisproject.

Abstract

Objective. Several studies have shown that expo-sure to opioids for short or long periods alters painsensitivity. Little is known about changes in painsensitivity during and after tapering of long-termprescribed opioid treatment in chronic low-back

pain (cLBP) patients.

Design. The goal of this prospective longitudinalstudy was to investigate pain sensitivity in a homo-geneous patient population (cLBP patients only)after tapering of long-term (17 months) opioid useand to monitor the changes in pain sensitivity for 6months.

Methods. Pain sensitivity (thermal sensation andthermal pain thresholds in low back and nondomi-nant hand) was measured by quantitative sensorytesting (QST) at 1 day before (T1), 3 weeks after (T2),

and 6 months after the start of opioid tapering (T3) in

35 patients with both cLBP and opioid medication(OP), 35 opioid-nave cLBP patients (ON), and 28individuals with neither pain nor opioid intake (HC).

Results. Significant differences in heat pain thresh-olds were found among the three groups at allthree time points (T1: P= 0.001, T2: P= 0.015, T3:P= 0.008), but not between the two patient groups.OP patients showed lower cold pain thresholdsat T2 than ON patients and HC. At T3, the heatpain thresholds of OP patients still remained lowerthan HC (P= 0.017), while those of ON patients werenormalized.

Conclusions. Our findings suggest that long-termuse of opioids does not reduce pain sensitivity incLBP patients; opioid tapering may induce briefhyperalgesia that can be normalized over a longerperiod.

Key Words. Opioid Tapering; Pain Sensitivity;Chronic Low-back Pain; Quantitative SensoryTesting

Introduction

To date, evidence of long-term amelioration of pain andimprovements in function attributable to opioid therapy is

lacking. Meta-analyses and systemic reviews of random-ized, double-blind, placebo-controlled trials of opioids for

chronic noncancer pain found these trials were of briefduration (average 5 weeks), subject to publication bias

from pharmaceutical company sponsorship, and limited

by eligibility criteria that excluded subjects with a historyof substance abuse [14]. Furthermore, patients on long-

term opioid treatment often complain of symptoms suchas agitation, sleep disturbance, nausea, emesis, consti-

pation, and cognitive disturbance, even hyperalgesia[510]. These studies showed that exposure to opioids

alters pain sensitivity. Angst et al. showed direct evi-dence in humans that short-term administration of an

Pain Medicine 2011; 12: 17201726Wiley Periodicals, Inc.

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opioid can enhance hyperalgesia, as observed during

withdrawal, and they pointed to a potential role of the

N-methyl-D-aspartate (NMDA)-receptor system in medi-ating such a hyperalgesic response. Compton et al.

confirmed the presence of hyperalgesia in four healthynon-opioid-dependent men using the acute opioid physi-

cal dependence (APD) model and showed that painthresholds and tolerance to the cold pressor uniformly

decreased across all APD induction methods. Thesefindings provide initial support for the existence of

opioid-induced hyperalgesia, which has been conceptu-

alized as a coexisting opponent process to opioid-induced analgesia and proposed to be an alternative

explanation for the development of analgesic toleranceto opioids.

To date, however, little is known about changes in pain

sensitivity during and after opioid tapering in chronic low-back pain (cLBP) patients treated with long-term opioids.

A previous study by our group compared the intensity ofpain before and after multidisciplinary pain therapy in

patients with cLBP who underwent opioid withdrawal. Thepain intensity via visual analog scale was significantly

decreased at discharge [11].

Another study of hyperalgesia under opioid withdrawaldemonstrated that 714 days after withdrawal 12 patients

showed decreased tolerance for cold in the cold pressortask, although their quality of life had significantly

improved [12]. A study using quantitative sensory testing(QST) suggested that the pain thresholds of pre-heroin-

dependent addicts were still different several months after

detoxification [13]. In contrast, some studies indicate that

the pain threshold values of chronic pain patients treatedwith opioids do not differ significantly from those of chronicpain patients treated with non-opioid analgesics [14].

Therefore, longitudinal studies are needed to resolve the

question of whether long-term opioid therapy and opioidtapering causes the increase in pain sensitivity reported in

chronic pain patients. The goal of this prospective longi-tudinal study was to investigate in a homogeneous patient

population (cLBP patients only) the long-term (17 months)

effects of opioid analgesics on pain sensitivity and tofollow for 6 months the changes in pain sensitivity during

opioid tapering and withdrawal. We used the QST tech-nique to assess pain sensitivity over a period of 6 months.

To our knowledge, this is the first longitudinal study of 6months duration regarding pain sensitivity during and

after opioid tapering.

Methods

Study Subjects

The study was approved by the ethics committee of theUniversity of Heidelberg, Germany and was funded by the

research fund of the Department of Orthopedic Surgery ofthe University of Heidelberg. The subjects were recruited

from the Department of Orthopedic Surgery, and all gaveinformed consent.

Three groups of subjects were studied: patients with both

cLBP and opioid therapy (group 1, N= 35); those whohad cLBP but had not been on opioid therapy for at least

3 months (group 2, N= 35); and healthy controls withneither pain nor opioid therapy (group 3, N= 28).

The inclusion criteria for patients with cLBP were as

follows: 1) age between 20 and 70 years; 2) a history of at

least 6 months of chronic myofascial low-back painwithout radicular sensory or motor deficits or radicular

pain symptoms (herniation or disc protrusion excluded bymagnetic resonance imaging), but sick leave amounting to

less than 6 months within the 12 months immediatelybefore enrolment in this study (grade II chronification

according to von Korff [15]); 3) opioid therapy was definedas intake of a morphine equivalent dose of at least 30 mg

per day every day for more than 3 months. For the stan-

dardized data analysis, we used the following conversionratios between an oral dose of morphine and other opioid

analgesics: 1 mg morphine = 0.65 mg oxycodone,0.25 mg methane, 5 mg tilidine, 0.01 mg fentanyl,

0.13 mg hydromorphone, 5 mg tramadol [16,17]; and 4)non-opioid pain medication in the group of opioid-nave

patients was allowed.

The exclusion criteria for both groups were: 1) sensorydeficits because of diabetes, alcoholic neuropathy, spinal

stenosis, or severe thyroid, liver, or kidney disease; 2)

interventional pain management procedures that mightalter QST responses, including neuraxial or local anes-

thetic block, within the previous 3 months; 3) major psy-

chiatric disorders requiring recent hospitalization, such asschizophrenia or psychosis; and 4) infection or acute injuryat the QST site.

Study Procedure

The study lasted 6 months (Figure 1). Before admission

into the study, each patient filled in a questionnaire giving

information on demographic data, pain location, painintensity on a numeric rating scale (NRS: 0 = no pain,10 = worst pain imaginable), pain pattern, pain duration,clinical diagnosis, and medications, including opioid and

non-opioid analgesics. During the whole study, all patientskept records of the medications they used.

Opioid Tapering Procedure

Upon admission to the study, the dosage of opioid prepa-ration was halved every 3 days until the patients became

opioid clean. In the first week, patients usually complainedof symptoms such as nausea, weakness, increased

sweating, or sleep disturbance. During the opioid taper-ing, doxepine was applied for damping of withdrawal

symptoms until 2 weeks after the patient had becomeopioid clean. All patients had stopped the use of opioids

by T2, and 85% of them remained opioid clean 6 monthsafter opioid withdrawal. Only data from these 85% were

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used for statistical analysis (group 1, N= 17; group 2,N= 22, group 3, N= 18); the remaining 15% of patientswho continued to use opioids at the 6-month time point

were considered as dropouts.

QST

QST was performed using the Thermal Sensory Analyzer

(TSA) II (Medoc Inc., Ramat Ishai, Israel) and was carriedout at three time pointsat admission into the study (T1)

and at 3 weeks (T2) and 6 months (T3) thereafterin a

quiet room maintained at 2025C. A contact thermode(3 3 cm) was gently attached and secured with a bandonto the lower back (bilaterally) and the nondominanthand in each subject. The baseline temperature was

32C. The cutoff temperatures were 0C and 50C. Eachsubject was told to stop stimulation as soon as he/she felt

a change in temperature. The measured parameters were:

cold sensation (CS), warm sensation (WS), cold painthreshold (CP), and heat pain threshold (WP).

Testing of CS and WS

Subjects were instructed to stop stimulation as soon asthey perceived an increase or decrease in temperature

from the baseline (32C). The testing was performed fourtimes in each patient.

Testing of CP and WP

Subjects were instructed to stop stimulation as soon asthey perceived a painful sensation as temperature

decreased (CP) or increased (WP) from the baseline tem-perature of 32C. The testing was performed three times

Intention-to-treat

99 patients

98 patients recruited

1 patient refused participation

35 opioid-positive

(Group 1)

35 opioid-nave

(Group 2)

28 healthy controls (HC)

(Group 3)

T1:

34 patients

1 patient excluded

(spinal claudication)

2 patients dropped out

(invalid QST values)

T1:

33 patients

T2:

32 patients

2 patients dropped out 4 patients dropped out

T2:

29 patients

T3:

20 patients


T3:

19 patients


T1:

22 HC

6 subjects dropped out

(invalid QST values)

Figure 1 Flow diagram of study participants during 6-month follow-up. T1 = day 0; T2 = day 21; T3 = day

180; HC = healthy controls; QST= quantitative sensory testing.

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in each patient. The temperature at which the subject

stopped the stimulation was recorded as threshold tem-

perature (C).

Statistical Analysis

According to the ShapiroWilk test, the values of QST

were not normally distributed, so nonparametric testswere used. As an overall test the Friedman test was

used for comparisons of the differences among the QSTresults among three time points. The Wilcoxon test

was used to compare differences of the QST results

between two time points. The overall KruskalWallis testwas used to compare the three unpaired groups, the

MannWhitney U-test for two groups. Spearmans rhoand Pearsons correlation coefficients were used to

examine the relationships between QST value and depres-sion, duration of pain, duration of opioid medication, dose

of opioids, and subjective pain intensity. Only completedatasets are included. All tests were performed with Sta-

tistical Package for the Social Sciences (SPSS) 17.0 soft-ware for Windows (SPSS Inc., Chicago, IL, USA). For each

statistical test, the significance level was set at P 0.05.

Bonferroni correction was used to correct for multipletesting.

Results

Table 1 shows characteristics of the subjects in all threegroups. Overall, there were no statistically significant dif-

ferences in age and sex among the groups. The depres-sion rate, the mean duration of pain, and pain medication

with nonsteroidal anti-inflammatory drugs and antidepres-

sants were comparable between OP and ON patients.The only differentiating characteristic between these two

groups was the intake of opioids.

There were significant differences in heat pain thresholdsat all three time points (KruskalWallis test: T1, P= 0.001;

T2, P= 0.015; T3, P= 0.008) among all three groups.However, this difference was confirmed only between

group 1 and group 3 at all time points (MannWhitney test:T1, P= 0.007; T2, P= 0.007; T3, P= 0.017) and betweengroups 2 and 3 at T1 (P= 0.001) and at T2 (0.002); therewas no difference between the two patient groups at any

time point (Figure 2A).

At T2, significant differences in CPs were found among allthree groups (KruskalWallis test: P= 0.003 for hand,P= 0.023 for left low back). The opioid-positive patients ofgroup 1 had a significant lower threshold to cold stimulithan patients in group 2 (P= 0.004 for hand) and healthycontrols (P= 0.001 for hand, P= 0.021 for left low back).Opioid-nave patients had a pain threshold similar to that

of healthy controls (Figure 2B).

Compared with T1, group 1 patients reacted to warmstimuli significantly faster at T2 (P= 0.029), while group 2patients did not change their pain profile. At T3, group 1

patients showed a further increase in speed of reaction towarm stimuli (P= 0.01) and a further lowering of CP(P= 0.026) relative to T2. Group 2 patients showed sig-nificant changes in heat pain thresholds (P= 0.028) at T3compared with T1.

No correlations between QST values and depression, painduration, opioid dose, or opioid duration were found. NRS

scores showed moderately significant correlations withthermal sensation, but not with pain thresholds. Statisti-

cally significant correlations were found between sensa-

tion of warmth in the hand and both age (r= 0.308,P= 0.015) and sex (r= 0.271, P= 0.003).

Discussion and Conclusions

This prospective study is the first to demonstrate the

changes of pain sensitivity in patients with cLBP underlong-term opioid use and opioid tapering in a longitudinal

Table 1 Characteristics of study subjects before therapy

Group 1 (N= 20) Group 2 (N= 19) Group 3 (N= 22) P-value

Age (year) 49.3 12.4 (3169) 46.6 8.9 (2865) 47.1 10.3 (3366) P> 0.05

Female 40.0% 63.2% 59.1% P> 0.05

Male 60.0% 436.8% 40.9%Diagnosis cLBP cLBP No pain

Depression 45.5% 42.5% 5% P> 0.05*

Other psychic comorbidity 20.5% 18.2% 0 P> 0.05*

Duration of pain (years) 10.3 10.5 7.3 5.6 0 P> 0.05*

Pain intensity (NRS) 6.23 1.9 5.3 2.3 0 P> 0.05*

Duration of opioid intake (months) 16.9 21.6 0 0

Morphine equivalent dose (mg/d) 107.3 77 0 0

Other pain medications NSAIDs (20%) NSAIDs (17.1%) 0 P> 0.05*

Antidepressants (17.1%) Antidepressants (3%)

* Comparison between patient groups.

cLBP = chronic low-back pain; NSAIDs = nonsteroidal anti-inflammatory drugs; NRS = numeric rating scale.

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setting. We found 1) that long-term (average 17 months)opioid use did not cause increased or reduced pain sen-

sitivity and 2) that opioid tapering leads to significantlydecreased pain thresholds as early as 3 weeks after opioid

tapering, but this effect is no longer present 6 months

later.

To our knowledge, this is the first longitudinal documen-

tation of opioid tapering-induced hyperalgesia in a homo-geneous patient population with cLBP under chronic

opioid medication with such a long observation period(mean 17 months). This finding correlates with those of

Prosser et al. [13] and indicates opioid-induced enhance-ment of hyperalgesia after opioid cessation. The mecha-

nisms of opioid tapering-induced hyperalgesia are poorlydescribed, especially in humans. One possible mecha-

nism of opioid tapering-induced hyperalgesia is the acti-

vation of central neuroimmune responses as described byRaghavendra et al. [18], who demonstrated that chronic

administration of morphine to sham-operated rats acti-vated spinal glia and upregulated proinflammatory cytok-

ines (interleukin [IL]-1b, IL-6, and tumor necrosis factor-a),which could mediate hyperalgesia. This neuroimmune

activation was further enhanced in nerve-injured rats after

chronic morphine treatment. Spinal inhibition of pro-inflammatory cytokines restored acute morphine antinoci-

ception in nerve-injured rats and also significantly reversedthe development of morphine tolerance and withdrawal-

induced hyperalgesia and allodynia in nerve-injured orsham-operated rats. Two years later, the same research

group investigated the effect of propentofylline, a glialmodulator, on the expression of analgesic tolerance and

withdrawal-induced hyperalgesia in chronic morphine-treated rats. They found that chronic morphine adminis-

tration through repeated subcutaneous injections inducedglial activation and enhanced pro-inflammatory cytokine

levels in the lumbar spinal cord [19].

Another study showed that during opioid abstinence-induced withdrawal, administration of glutamate receptorantagonists and the kappa agonist to the nucleus raphe

magnus suppressed the withdrawal-induced hyperalge-sia, which is thought to be mediated by activation of those

pain-facilitating neurons during opioid withdrawal [20].

Finally, the withdrawal of chronic opioid use could inducesensitization of spinal NMDA receptors, presynaptic/

central glutamate receptors, and peripheral a2-adrenergic/adenosine receptors, thus decreasing the painthresholds to stimuli and causing the hyperalgesia.

Our results showed that the pain thresholds of opioid-

positive and opioid-nave patients did not differ from eachother at T1. Compared with healthy subjects, both opioid-

positive and opioid-nave patients had significantlydecreased pain thresholds to heat stimuli. This indicates

that low-back pain itself might induce peripheral sensiti-

zation [21], which seems not to be counteracted by opioidmedication, as shown in our study and by other authors

[22,23]. In contrast, long-term opioid therapy (in our studythe mean duration of opioid use was 17 months) intensi-

fied the peripheral sensitization rather than reducing it.

Potential confounding factors were considered in thisstudy. We tested both healthy controls and opioid-nave

WP

40

A

B

T1 T2 T3

T1 T2 T3

41

42

43

44

45

46

47

Time

TemperatureC

group 1

group 2

group 3

*** ** ** **

*

CP

0

2

4

6

8

10

12

14

16

18

Time

TemperatureC

group 1

group 2

group 3

** **

*

Figure 2 Pain thresholds as measured by quantitative

sensory testing in patients with chronic low-back pain.

* P< 0.05; ** P< 0.01; T1 = day 0; T2 = day 21;

T3 = day 180. Group 1: Patients with chronic low-back

pain and under opioid therapy before study; group 2:

patients with chronic low-back pain without opioid

therapy before study; group 3: healthy controls. (A)

Heat pain thresholds (WP). Both patient groups

showed significantly lower WP than healthy controls at

T1 and T2. At T3, group 1 still had lower WP than group

3 but in group 2 pain sensitivity had improved signifi-

cantly after 6 months. (B) Cold pain thresholds (CP). AtT2 but not at T1 or T3, the CP were significantly

different between groups 1 and 2 and between groups

1 and 3. Group1 patients were more sensitive to cold

stimuli, and perceived the same cold stimuli as pain

earlier, than those in group 3.

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patients and used their baseline QST responses to ensure

differentiation of QST findings because of opioid usage or

to preexisting low-back pain. The palm of the hand wasadditionally chosen as a control region to enable detection

of any opioid-induced hyperalgesia independent of preex-isting low-back pain [24].

To rule out any influence of fluctuations in ambient tem-

perature on QST results, the temperature of the roomwhere QST was carried out was kept stable at 2025C

during testing [25,26].

Age and sex influenced the perception of warmth in our

study, so we considered both as potential confoundingfactors. All three groups turned out to be comparable for

age and sex. Both of the two persons conducting thetests were female, excluding sex of the test person as

confounding factor [27,28]. Duration of pain, pain intensity,comorbidity with depression, and use of antidepressants

were all similar in both patient groups. We found no cor-

relation between depression score and QST parametersat any time point.

We found in this study that subjective pain intensity cor-

related with objective thermal perception, in agreementwith our previous results [11] Correspondingly, we

observed that heat pain thresholds of opioid-positivepatients did not change over the whole study, even at the

end of the follow-up period when patients were alreadyopioid clean. This indicates that it is not pain thresholds

with QST but rather thermal sensation that determinespatients subjective pain intensity, as previous studies

have reported [19,29].

In conclusion, this study makes two important observa-tions. First, it confirms that cLBP patients demonstrateheat hyperalgesia when nociception is measured using

QST. Opioid exposure additionally changes the thermalsensation in this patient population. Second, it shows that

opioid tapering may induce cold hyperalgesia shortly afterdose reduction but that this effect disappears after long-

term (6 months in our study) abstinence from opioids.

Acknowledgments

We would like to acknowledge financial support from the

Orthopedic University Hospital, University of Heidelberg,Germany.

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