Scholarly article on topic 'Long-term use of opioids in 210 officially registered patients with chronic noncancer pain in Taiwan: A cross-sectional study'

Long-term use of opioids in 210 officially registered patients with chronic noncancer pain in Taiwan: A cross-sectional study Academic research paper on "Clinical medicine"

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{"chronic pain" / noncancer / opioid}

Abstract of research paper on Clinical medicine, author of scientific article — Tso-Chou Lin, Luo-Ping Ger, Joseph V. Pergolizzi, Robert B. Raffa, Ju-O Wang, et al.

Background/purpose Prescribing opioids for chronic noncancer pain has been strictly regulated for two decades in Taiwan. The aim of this study was to survey the patients' perspectives and potential drawbacks following long-term use of opioids. Methods An observational cross-sectional survey using the Taiwanese version of Brief Pain Inventory was conducted among outpatients with chronic noncancer pain registered by the Taiwan Food and Drug Administration. Patients were also asked about their sexual behavior, depression, opioid misuse behaviors, and use of complementary and alternative medicine. Results For 210 of 328 outpatients (64.0%), the median pain duration was 96 months and opioid treatment duration was 57 months. The median morphine equivalent dose was 150 mg/d, with 30.5% of patients exceeding the daily watchful dose, defined as 200 mg of morphine equivalent dose. Pain reduction after taking opioids was ∼50% in the past week. The top three diagnoses were chronic pancreatitis, spinal cord injury, and neuralgia. The leading side effects were constipation (46.7%), and decreased sexual desire (69.5%) and satisfaction (57.9%). Depression was currently diagnosed in 55.2% of patients. Twenty patients (9.5%) displayed at least one aberrant behavior in the past month. Only 76 (36.2%) patients had ever received nerve block procedures, and 118 (56.2%) tried complementary and alternative medicine. Conclusion This nationwide survey described the concurrent pain intensity, daily function, and various adverse effects by long-term opioids among 210 monitored outpatients with chronic noncancer pain in Taiwan. More efforts are suggested to reduce opioid prescriptions in the 30% of patients exceeding daily watchful dose.

Academic research paper on topic "Long-term use of opioids in 210 officially registered patients with chronic noncancer pain in Taiwan: A cross-sectional study"

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Journal of the Formosan Medical Association (2016) xx, 1-9

ORIGINAL ARTICLE

Long-term use of opioids in 210 officially registered patients with chronic noncancer pain in Taiwan: A cross-sectional study

Tso-Chou Lin a, Luo-Ping Ger b, Joseph V. Pergolizzi Jr c, Robert B. Raffa d, Ju-O Wang e, Shung-TaiHo f *

a Department of Anesthesiology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

b Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

c Naples Anesthesia and Pain Associates, Naples, FL, USA

d Department of Pharmaceutical Sciences, School of Pharmacy, Temple University, Philadelphia, PA, USA

e Department of Education and Research, Taipei City Hospital-Renai Branch, School of Public Health, National Defense Medical Center, Taipei, Taiwan

f Department of Anesthesiology, Taipei Veterans General Hospital, National Defense Medical Center, Taipei, Taiwan

Received 26 August 2016; received in revised form 30 October 2016; accepted 31 October 2016

Background/Purpose: Prescribing opioids for chronic noncancer pain has been strictly regulated for two decades in Taiwan. The aim of this study was to survey the patients' perspectives and potential drawbacks following long-term use of opioids.

Methods: An observational cross-sectional survey using the Taiwanese version of Brief Pain Inventory was conducted among outpatients with chronic noncancer pain registered by the Taiwan Food and Drug Administration. Patients were also asked about their sexual behavior, depression, opioid misuse behaviors, and use of complementary and alternative medicine. Results: For 210 of 328 outpatients (64.0%), the median pain duration was 96 months and opioid treatment duration was 57 months. The median morphine equivalent dose was 150 mg/d, with 30.5% of patients exceeding the daily watchful dose, defined as 200 mg of morphine equivalent dose. Pain reduction after taking opioids was ~50% in the past week. The top three diagnoses were chronic pancreatitis, spinal cord injury, and neuralgia. The leading side effects were constipation (46.7%), and decreased sexual desire (69.5%) and satisfaction (57.9%). Depression was currently diagnosed in 55.2% of patients. Twenty patients

Conflicts of interest: The authors have no conflicts of interest relevant to this article.

* Corresponding author. Department of Anesthesiology, Taipei Veterans General Hospital, 3F, Chung-Cheng Building, Number 201, Section 2, Shipai Road, Taipei City 112, Taiwan.

E-mail address: stho@vghtpe.gov.tw (S.-T. Ho).

http://dx.doi.org/10.1016Zj.jfma.2016.10.015

0929-6646/Copyright © 2016, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

KEYWORDS

chronic pain;

noncancer;

opioid

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2 T.-C. Lin et al.

(9.5%) displayed at least one aberrant behavior in the past month. Only 76 (36.2%) patients had ever received nerve block procedures, and 118 (56.2%) tried complementary and alternative medicine.

Conclusion: This nationwide survey described the concurrent pain intensity, daily function, and various adverse effects by long-term opioids among 210 monitored outpatients with chronic noncancer pain in Taiwan. More efforts are suggested to reduce opioid prescriptions in the 30% of patients exceeding daily watchful dose.

Copyright © 2016, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

All chronic pain disorders outside of cancer pain or pain at the end of life are collectively labeled "chronic noncancer pain" (CNCP).1 Prescribing opioids for CNCP started in the late 1990s2 and became widespread when it was shown to be effective in numerous randomized controlled trials of CNCP patients.3 However, the long-term use of opioids has become increasingly controversial owing to concerns about efficacy for pain relief, daily life function, and tolerance.4 Prescription opioid misuse/abuse and associated morbidity and mortality are additional concerns.5 Despite the widespread use of opioids, significant research gaps exist with limited data from observational or epidemiological studies about long-term use of opioids in CNCP patients.4'6-12

Taiwan began to reform its universal National Health Insurance program in 1995. Comprehensive coverage for more than 99% of Taiwan's 23 million population was achieved in 2007,13 including cancer patients14 and registered CNCP patients who were vulnerable to unemployment because of their chronic pain. Chronic opioid treatment has been strictly regulated in Taiwan since 1996, and each CNCP outpatient is required to be assessed by the hospital's opioid committee following consultations with an anesthesiologist or a pain specialist, a psychiatrist, and other relevant specialists, and eventually approved by the Taiwan Food and Drug Administration for legal long-term use of opioids.15 Oral (morphine or meperidine) and transdermal (fentanyl) prescriptions for strong opioids are limited to 2 weeks, whereas prescriptions for opioid injections must be renewed weekly. Every 4 months, the treating hospital is expected to submit a report on opioid therapy with patient evaluations to the Taiwan Food and Drug Administration for surveillance. Patients with aberrant behaviors suggestive of possible opioid misuse or abuse must be reported to the hospital committee for determination of discontinuation of opioid treatment.15

In 2001, we first interviewed 61 registered CNCP patients in Taiwan,7 who were compliant to chronic opioid therapy and obtained improved pain relief and daily function. Based on a 55% increase in opioid consumption in Taiwan from 2002 to 2007,13 this study was undertaken to interview the growing population of noncancer pain patients in Taiwan16 for their concurrent perceptions of pain relief and adverse effects by chronic opioid treatment, including drug misuse, daily function, depression, and sexual activity.

Methods Participants

After obtaining approval and a grant from the Taiwan Food and Drug Administration in January 2010, all 328 registered CNCP patients were included in this study. To protect the patients' privacy, the list omitted the patients' Chinese first names and excluded their personal identification numbers, addresses, and telephone numbers, but contained the names of their treating physicians and hospitals. In the following 8 months, the study interviewers (the physician investigator or a trained research assistant) visited the outpatient departments of these hospitals and requested that the treating physicians identify the patients and their conditions. Patients were then briefly interviewed to determine their interest in this study. After signing the written informed consent approved by the Tri-Service General Hospital Institutional Review Board (TSGHIRB-098-05-254), Taipei, Taiwan, participants completed the questionnaires by themselves or with verbal help from the interviewer.

Study instrument

The Chinese language questionnaire was largely based on prior similar surveys1'7'17'18 but refined to achieve greater content validity by the review committee of six senior specialists with expertise in CNCP management, including one pain specialist experienced with clinically managing CNCP outpatients, one neurologist, one neurosurgeon, one psychiatrist, one physician—lawyer, and one epidemiologist. The first section of the questionnaire included the Taiwanese version of Brief Pain Inventory,18 which uses a numeric scale of 0 to 10 in order to evaluate pain intensity at its worst (10), least (0), and on average in the past week along with how pain interferes with daily function, including general activities, mood, ability to walk, normal work activities, relationships with other people, sleep, and enjoyment of life prior to and after taking opioids. The survey also asked the patient's reduction in pain intensity, stated as a percentage, after taking opioids in the past week. Adverse effects were recorded and opioid prescriptions were verified by the treating physicians at the outpatient departments and converted to a daily oral morphine equivalent dose (MED).19 Thus, oral morphine 30 mg was equivalent to 10 mg of intramuscular morphine

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whereas 200 mg of oral codeine was equivalent to 300 mg of oral meperidine or 75 mg of intramuscular meperidine, and transdermal fentanyl 100 mg/h was equivalent to 360 mg/ d of oral morphine. The Canadian guideline for safe and effective use of opioids suggests a careful reassessment if the dose approaches 200 mg MED (the so-called "watchful dose").19 The second section of the questionnaire asked about aberrant behaviors associated with opioid prescription misuse in the past month,1 and self-reported impacts on sexual function (desire, frequency, capability, and satisfaction). The use of complementary and alternative medicine, such as acupuncture, herbal drugs, and/or chiropractic, was queried along with its effectiveness. In the third section of the questionnaire, the Chinese version of Beck Depression Inventory was used in order to evaluate each patient's depressive condition in the past week.7

Statistical analysis

The results of the questionnaire were entered into SPSS version 17 (SPSS Inc., Chicago, IL, USA). The demographic data were presented as mean ± standard deviation. Pain severity and interference scores were analyzed between different time and patient groups by using paired t test, t test, or one-way analysis of variance. Adverse effects, use of complementary and alternative medicine, and depressive status were examined as categorical variables by using the c2 test. The Kruskal—Wallis one-way analysis of variance and Mann—Whitney U test were used to compare the MEDs among diagnoses, side effects, sexual desire, and depressive score. In addition, the association between pain intensity and depression score was evaluated by Pearson's correlation. In all cases, a p value < 0.05 was considered statistically significant.

Results

A total of 210 (64.0%) of the 328 registered CNCP patients completed the questionnaires (Figure 1). Eleven (3.4%) patients declined to participate in this survey, and another 107 (32.6%) patients did not come back to the outpatient departments during the study period according to their physicians, including 38 (11.6%) who had reduced or discontinued opioid treatment, 12 (3.7%) who died, two (0.6%) who were incarcerated, and 55 (16.8%) who were lost to follow-up.

Table 1 presents the demographic data, details of opioid prescriptions, and pain intensity scores. Of the 210 patients, there were 51 (24.3%) in the age range of 20—39 years, 128 (60.9%) in the age range of 40—64 years, 17 (8.1%) in the age range of 65—79 years, and 14 (6.7%) older than 80 years. Of the 113 (53.8%) unemployed patients, 109 (51.9%) were younger than 65 years. In total, 109 (51.9%) patients ascribed their unemployment or retirement to chronic pain. The median durations of pain and opioid treatment were 96 months and 57 months, respectively, whereas a 54-year-old woman suffering from a spinal cord injury with neuropathic pain had the longest durations at 372 months and 240 months, respectively. In the past week, the mean pain score was 6.1 and the mean overall pain reduction was 49.6% after taking opioids. The mean oral

Figure 1 Flow diagram of participants at the outpatient departments.

MED (n = 202) was 176.5 (median 150) mg/d, except for eight patients receiving opioids that had not been converted into MEDs (nalbuphine, tramadol, buprenorphine, and a combination of tramadol and buprenorphine in 1 patient, 2 patients, 4 patients, and 1 patient, respectively). The highest three MEDs were 1100 mg/d, 910 mg/d, and 740 mg/d and came from the fentanyl patch (300 mg/h), and sustained-release oral morphine 30 mg and 60 mg, respectively. Just less than a third of patients (64/210, 30.5%) took daily MEDs that surpassed the watchful dose of 200 mg, whereas the top 5% (10/210) of patients accounted for 19.2% (6840/35,623) of the total daily MED. Among the 14 patients who were older than 80 years, the median duration of opioid treatment was 60 months. They had insignificantly lower MEDs (124.3 ± 101.2 mg/d, range 4.5-300 mg/d, median 105 mg/d, p = 0.199), and comparable worst (8.1 ± 1.7, p = 0.324), least (3.9 ± 2.8, p = 0.624), and average (6.0 ± 2.3, p = 0.810) pain scores, as compared with those aged younger than 80 years. In total, four (28.7%) of them were receiving opioids more than 200 mg MED (210 mg, 240 mg, 270 mg, and 300 mg).

As shown in Figure 2, the mean score of functional interference was significantly reduced from 7.7 to 4.2 after taking opioids in the past week, including significant improvements in general activity (7.9-4.0), mood (7.9-4.3), walking ability (7.6-4.2), ability to carry out normal work (7.7-4.3), relationships with other people (7.3-4.0), sleep (8.4-4.7), and enjoyment of life (7.2-4.1).

Table 1 General data and pain intensity (n = 210, 142 men and 68 women).3

Mean ± SD Range Median

Age (y), n = 210 50.0 ± 14.6 21-88 46

Pain duration (mo), n = 210 112.8 ± 70.2 24-372 96

Opioid therapy (mo), n = 210b 63.7 ± 45.2 12-240 57

Morphine equivalent dose, oral (mg/d), n = 202 176.5 ± 157.4 4.5-1100 150

Morphine, intramuscular (mg/d), n = 25 17.2 ± 11.4 10-60 10

Morphine 10 mg, oral (mg/d), n = 84 58.6 ± 58.7 10-300 40

MST (30 mg), oral (mg/d), n = 70 124.3 ± 120.8 30-900 90

MST (60 mg), oral (mg/d), n = 49 204.9 ± 123.0 60-720 180

Meperidine, oral (mg/d), n = 7 164.3 ± 69.0 100-300 150

Meperidine, intramuscular (mg/d), n = 23 89.1 ± 70.6 50-300 50

Fentanyl, transdermal (mg/h), n = 53 50.2 ± 40.5 12.5-300 50

Codeine, oral (mg/d), n = 11 105.0 ± 39.3 60-180 105 Pain intensityc

Onset, prior to chronic opioid therapy 8.4 ± 2.1 1-10 9

Worst, in the past wk 8.5 ± 1.7 2-10 9

Least, in the past wk 3.6 ± 2.1 0-10 3

Average, in the past wk 6.1 ± 2.0 1-10 6

Pain reduction (%) after taking opioids, in the past wk 49.6 ± 19.4 0-100 50

MST = morphine sustained release; SD = standard deviation. a Meperidine, intramuscular, was prescribed to 23 patients because of intolerable side effects by previous oral morphine prescription. b Only three potent opioids (morphine, meperidine, and fentanyl) were available in Taiwan in 2010. Transdermal fentanyl patch was first introduced into Taiwan in 2001. c Pain intensity, 0 = no pain and 10 = pain as bad as you can imagine.

Table 2 lists the CNCP diagnoses, daily MEDs, and daily function interference. The leading three diagnoses were chronic pancreatitis (n = 44), spinal cord injury (n = 44), and neuralgia (n = 27), amounting to 115 (54.8%) of the patient population. The highest MED of 1100 mg/d involved transdermal fentanyl 300 mg/h for a patient with chronic pancreatitis, whereas the lowest MED of 4.5 mg/d came from codeine 30 mg/d for one purpura patient. There were no significant differences regarding daily MED (p = 0.072) and average pain score (p = 0.312) in the past week among patients with various diagnoses. Those with abdominal pain reported the lowest average score (1.8/10) of interference with daily function after taking opioids (p = 0.001), but the reduction of interference scores prior to and after taking opioids were insignificant between diagnoses (p = 0.632).

0 Before ■ After taking opioids 10 - T T t T T

General Mood Walking Normal Relation- Sleep Enjoyment activity ability work ship of life

Figure 2 The mean scores of pain interference with daily function were significantly reduced after taking opioids in the past week, with all p < 0.001.

As shown in Table 3, 146 (69.5%) of 210 patients reported reduced sexual desire. More than half of 133 sexually active patients reported decreases in sexual performance (57.9%), frequency (55.6%), and satisfaction (57.9%).

Up to 116 (55.2%) patients had a current diagnosis of depression, including nine (4.3%) patients who were diagnosed prior to their chronic pain and 107 (50.9%) patients diagnosed after. The depression scores (Table 4) for the past week revealed moderate or severe depressive status in 72 (34.3%) patients, which were not correlated with their daily MEDs. However, the patients with minimal depressive status had significantly lower pain scores for the worst pain, the least pain, and on average. Using Pearson correlation analysis, depression scores could be significantly associated with worst pain scores, the least pain scores, and average pain scores (r = 0.253, p < 0.001).

The most frequently reported side effects of chronic opioid therapy were constipation (46.7%), dry mouth (18.1%), and nausea and vomiting (12.4%), which were also the most intolerable side effects reported by patients (30.5%, 6.7%, and 4.8%, respectively). These side effects were not significantly associated with the daily MEDs when compared to patients without such side effects (197.1 vs. 157.6 for constipation, 196.8 vs. 171.6 for dry mouth, and 208.0 vs. 172.3 for nausea and vomiting).

Opioid misuse and associated aberrant behaviors were also investigated. Twenty (9.5%) patients said they had used their pain medicine for symptoms other than pain (e.g., to help sleep, improve mood, or relieve stress). Only two (1.0%) patients said they had ever borrowed pain medication from someone else (and reported they did so rarely), and 14 (6.7%) stated they had visited emergency rooms for additional opioid analgesics in the past month. Twenty (9.5%) patients said they had lost their opioid

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CNCP patients with long-term opioids 5

Table 2 Diagnoses of chronic noncancer pain and the opioid doses, pain scores, and interference with daily function (n = 210, 142 men/68 women).a

Diagnosis N (Men/women) Morphine equivalent Pain intensity13 Interference with

dose* (mg/d) daily functionc

Mean ± SD (range) Median Worst Least Average** Before After*** Reduction****

Chronic pancreatitis 44 (40/4) 189.2 ± 184.7 (10-1100) 150 8.3 3.2 5.9 6.9 2.8 4.0

Spinal cord injury 44 (28/16) 202.2 ± 171.0 (20-740) 180 8.8 4.1 6.3 8.1 4.8 3.3

Neuralgia 27 (18/9) 160.3 ± 172.0 (10-910) 120 8.5 3.3 6.0 7.4 4.3 3.1

Failed back surgery 20 (13/7) 156.3 ± 127.7 (30-480) 120 9.3 3.9 6.9 8.8 5.2 3.6

syndrome

Joint pain 16 (11/5) 176.8 ± 111.9 (9-420) 180 8.6 3.3 5.6 8.0 4.3 3.7

Phantom pain 13 (10/3) 226.2 ± 102.0 (30-380) 220 7.8 3.8 5.8 9.0 5.5 3.5

Complex regional 10 (7/3) 222.2 ± 209.3 (10-690) 120 9.1 4.3 6.6 8.0 4.4 3.6

pain syndrome

Diabetic neuropathy 7(6/1) 141.3 ± 136.0 (9-360) 120 6.4 2.6 4.9 6.2 3.6 2.6

Fibromyalgia 7 (0/7) 115.4 ± 78.5 (18-270) 100 8.3 3.9 7.1 7.5 3.9 3.6

Chronic 6 (5/1) 206.0 ± 222.1 (30-580) 160 8.9 4.0 6.9 8.1 4.9 3.2

osteomyelitis

Abdominal pain 5 (2/3) 126.0 ± 39.7 (60-160) 140 8.0 1.8 5.2 6.1 1.8 4.3

Othersd 11 (2/9) 73.9 ± 78.3 (4.5-210) 30 8.5 3.7 6.2 8.1 5.0 3.1

The p values are based on the Kruskal-Wallis one-way analysis of variance for morphine equivalent doses (*p = 0.072), average pain scores (**p = 0.312), average interference scores after taking opioids (***p = 0.001), and the reduction of interference scores (****p = 0.632) after taking opioids between diagnoses. SD = standard deviation.

a The data of pain intensity and interference with daily function in the past week are presented as mean. b Pain intensity: 0 = no pain and 10 = pain as bad as you can imagine. c Interference: 0 = does not interfere and 10 = completely interferes.

d Others, including burn (3 patients), chronic obstructive pulmonary disease with chronic cough (3 patients), migraine (1 patient), skin lesion (1 patient), dermatomyositis (1 patient), and purpura (2 patients).

medications more than once, and 12 (5.7%) said they had taken opioid medications from resources other than the hospital prior to receiving opioid therapy.

Seventy-six (36.2%) patients had ever received nerve block procedures, 29 (13.8%) ever had local anesthetic injection, and 10 (4.8%) ever experienced epidural analgesia. Only seven (3.3%) patients could recognize the concomitant antidepressants and nine (4.3%) took anticonvulsants, aside from 142 (67.6%) who were not aware of the types of oral nonopioid analgesics they had ever received. The use of complementary and alternative

medicine was documented, including traditional Chinese medicine, which is popular in Taiwan. As many as 118 (56.2%) patients had used some forms of complementary and alternative medicine, including 112 (53.3%) patients who had visited traditional Chinese medicine doctors and 95 (45.2%) patients who took herbal remedies. Patients also reported using acupuncture (31.9%), massage (20.5%), chiropractic care (19.5%), and martial arts (10%). The majority of these patients (109/118, 92.4%) reported little or no pain relief by complementary and alternative medicine.

Table 3 Interference with sexual desire and activity after chronic opioid therapy (n = 210, 142 men/68 women).

Itemsa n/N (%) Men/women Morphine equivalent dose (mg/d)

Mean ± SD Median (range) p

Sexual desire

Decreased 146/210 (69.5) 98/48 190.4 ± 181.7 160 (4.5-1100) 0.796a

Increased 2/210 (0.1) 0/2 130.0 ± 70.7 130 (80-180)

No change 62/210 (29.5) 44/18 178.8 ± 162.2 120 (9-720)

Without sexual activity 77/210 (36.7) 48/29 200.2 ± 188.2 180 (9-1100) 0.214b

With sexual activity 133/210 (63.3) 94/39 178.6 ± 167.5 120 (4.5-980)

Decreased capability 77/133 (57.9) 54/23 230.8 ± 230.6 180 (10-1100)

Decreased frequency 74/133 (55.6) 59/25 220.0 ± 223.9 180 (10-1100)

Decreased satisfaction 77/133 (57.9) 54/23 207.1 ± 205.9 180 (10-1100)

SD = standard deviation.

a The p value is based on Kruskal-Wallis one-way analysis of variance for morphine equivalent doses between sexual desire. b The p value is based on Mann-Whitney U test for morphine equivalent doses between with and without sexual activity.

Table 4 Beck Depression Inventory scores among patients receiving long-term opioids for chronic noncancer pain (n = 210, 142 men/68 women).

Depression N (%) Men/ Morphine equivalent dose (mg) Pain intensity

score women Mean ± SD Median (range) p Worst p Least p Average p

0-9 (minimal) 78 (37.1) 58/20 166.7 ± 132.9 140 (10-690) 0.922a 8.3 ± 1.8* 0.039b 3.2 ± 2.1** 0.012b 5.7 ± 2.0*** 0.006b 10-18 (mild) 60 (28.6) 42/18 179.8 ± 158.7 160 (13.5-910) 8.4 ± 1.8 3.4 ± 1.9 6.1 ± 2.0

19-29 36 (17.1) 24/12 180.8 ± 204.9 165 (4.5-1100) 8.4 ± 1.8 4.0 ± 2.0 6.2 ± 1.9

(moderate)

More than 30 36 (17.1) 18/18 187.3 ± 157.3 135 (9-740) 9.3 ± 1.2* 4.5 ± 2.2** 7.1 ± 1.7***

(severe)

By further Scheffe test, p values were *p = 0.046; **p = 0.029; and ***p = 0.006. SD = standard deviation.

a The value was based on Kruskal-Wallis one-way analysis of variance for morphine equivalent doses between depression scores. b Values were based on the Kruskal-Wallis one-way analysis of variance for pain intensity scores between depression scores.

Discussion

Among the 210 screened and monitored CNCP outpatients who were compliant to long-term use of opioids, this survey revealed the concurrent pain relief and daily function improvement after taking opioids in the past week, but with considerable adverse effects, such as constipation, depression, and decreased sexual desire and satisfaction in up to 50% of them. Despite being under strict surveillance, close to 10% of patients self-reported opioid drug misuse or aberrant behaviors. Notably, 30.5% of patients received opioids exceeding the daily watchful dose, defined as MED of 200 mg or more.

Our previous report investigated 61 (53.5%) of 114 Taiwan registered CNCP patients in 2001.7 The present study includes a larger number of patients with a longer median duration of opioid administration (30 months vs. 57 months). In both studies, patients had comparable and significant reductions in pain intensity and interference with daily function after receiving opioid therapy. In this study, a 50% pain reduction was reported after taking opioids in the past week. In general, a > 30% reduction of pain intensity and interference is considered to be effective for CNCP management.20 However, pain intensity ratings are not necessarily a simple reflection of tissue damage or sensation intensity in patients with chronic pain.21 Applying interdisciplinary and multimodal treatments, such as coping and acceptance strategies, may primarily reduce the suffering associated with pain and then secondarily reduce pain intensity and interference with daily life function.

Since the late 1990s, the increased prescribing of opioids was accompanied by a marked increase in opioid-related morbidity and mortality,2 which is sometimes correlated to dose. Doses varied in our study among patients and in comparison to the literature. Up to 30.5% of our patients were taking more than 200 mg MED/d, which is defined as a daily watchful dose by the Canadian guideline for safe and effective use of opioids for CNCP.19 By contrast, Mailis-Gagnon et al8 reported that 19% of 455 Canadian CNCP outpatients in a tertiary care pain clinic were receiving opioids in excess of the daily 200 mg MED watchful dose. However, the median MED in our study, 150 mg/d (range, 4.5—1100 mg/d), was generally lower than that in the

previous report of 84 Canadian patients who had a median dose of 220 mg/d (range, 20—1990 mg/d).9 As expected, the MEDs of 14 geriatric patients (older than 80 years) in this study were generally lower than those of patients younger than 80 years, but without significance and with comparable pain scores. Nevertheless, four (28.6%) of the patients were receiving a watchful MED exceeding 200 mg/ d. Despite strict opioid regulations in Taiwan, more efforts, including interventional procedures and physician educa-tion,22 are necessary to reduce the harms associated with long-term and high-dose opioid prescriptions.

Long-term opioid use tends to be heavily concentrated among a small percentage of patients. Edlund et al23 reported that the top 5% of opioid users accounted for 48% of total MED dose in one state-based, publicly insured (Arkansas Medicaid, US) population, and 70% in one national, commercially insured (HealthCore, US) population. In our results, the top 5% of users consumed much less opioid (19.2% of the total MED amount among these Taiwan officially registered patients). It appears that the overall lower MEDs in our CNCP population accounted for the lower MED consumption by the top 5% of opioid users in Taiwan. There were no significant associations between the MEDs in our study and diagnoses, side effects, sexual desire, or depression scores.

In Taiwan, only three strong opioids—oral or intramuscular morphine, the transdermal fentanyl patch, and oral or intramuscular pethidine (meperidine)—were available for the registered CNCP outpatients in 2010,13'24 whereas oxycodone and hydromorphone became legally available in May 2015.15 It should be noted that in our study there were 23 patients who were switched from oral morphine to intramuscular meperidine because of intolerable side effects from morphine. These prescriptions should have been discontinued in 2011 because the Taiwan Food and Drug Administration in a clinical guideline had determined that meperidine use for chronic pancreatitis or chronic pain is "not recommended or inappropriate usage."25 Nevertheless, these outpatients reported no symptoms related to the excitatory metabolite normeperidine and received weekly intramuscular meperidine prescriptions under surveillance.

In our study population, almost 70% reported reduced libido, with decreased sexual activity and less sexual

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satisfaction. Opioids suppress the hypothal-amic-pituitary-gonadal axis. Both men and women taking opioids have lower free testosterone levels,26,27 but these levels cannot be correlated to the frequency of sexual dysfunction.28 Adequate serum testosterone levels have an appreciable role in both males and females for libido and sexuality, cellular growth, maintenance of muscle mass and bone, healing, blood-brain barrier function, and central nervous system maintenance.29 Regardless of age or disease etiology, men with a total testosterone level of less than approximately 300 ng/dL (10.4 nmol/L) often develop signs and symptoms associated with classic hypogonadism,30 which could be improved by testosterone replacement in those with opioid-induced androgen deficiency.31 In actual clinical practice, such sex hormone testing is very rare in pain centers.29 Owing to a paucity of literature regarding both controlled and observational endocrine effects of most opioids,27'31 further studies are necessary to elucidate the ranges of testosterone concentrations among CNCP patients and rule out the possible sexual adverse effects produced by other comorbidities, such as unrelieved depression or diabetes mellitus, which can result in neuropathy associated with sexual dysfunction.

Earlier recognition of undesired effects of long-term opioid use is essential, in that side effects can limit treatment. In fact, a meta-analysis revealed that many patients withdrew from opioid-related clinical trials because of intolerable adverse effects (32.5% oral; 6.3% intrathecal; and 17.5% transdermal), with the most commonly reported side effects being gastrointestinal (i.e., constipation, nausea, and dyspepsia).32 Opioid-induced constipation develops in 40-95% of CNCP patients and approximately half of the patients treated with laxatives do not improve,33 because laxatives do not target the underlying cause of constipation (opioid-binding mu receptors in the enteric system). Nevertheless, in an effort to obtain pain relief, many CNCP patients endure constipation symptoms that limit their work productivity and overall health-related quality of life and adhere to treatments that provide little relief.34 In this study, constipation was the most frequent side effect (reported by 46.7% of patients) and considered to be the most intolerable (30.5%). Further education and research are necessary to identify and provide more efficacious constipation therapies for the CNCP patient population.

Chronic pain patients with concomitant psychological disorders tend to use more opioids8 and are at increased risk for prescription opioid misuse.35 Pretreatment psychological screening and ongoing support is crucial for a good outcome to opioid therapy and to prevent opioid abuse.6 According to the Taiwan official opioid regulation,15 registered CNCP patients should receive an initial psychiatric consultation, which should encompass the patient's psychiatric status, any comorbid psychiatric disorders, medication history, and history of drug abuse. If the treating physician notices any aberrant behaviors by the registered CNCP patient, such as drug hoarding, the physician must investigate immediately and report it to the opioid committee for handling. Opioid therapy may be discontinued in severe cases. In this study, most respondents complied with the official regulation, and there were very few behaviors associated with prescription drug

misuse. However, aberrant behaviors might have been underestimated in our study, in that 118 (36.0%) patients declined or withdrew from outpatient follow-up, including two patients who were in prison and 55 patients lost to follow-up. However, the abuse rates in other studies of CNCP patients are likewise low. One meta-analysis revealed that signs of opioid addiction were reported in only 0.05% (1/2042) of CNCP patients and abuse in only 0.43% (3/ 685).32 Another meta-analysis reported the calculated abuse/addiction rate of 3.27% and the aberrant drug-related behaviors rate of 11.5%, which were reduced to 0.19% and 0.59%, respectively, among those preselected CNCP patients without previous or current history of abuse/ addiction.36 Urine drug testing has become a widely used tool for detecting and deterring illicit drug use in the United States37 and in Taiwan, but it is not yet regularly used in registered CNCP patients. For the Taiwan care providers, more education on the symptoms or signs of prescription drug misuse is needed in the future.

This uncontrolled and nonblinded cross-sectional study has several limitations. First, the intolerable side effects reported by our CNCP patients might have been underestimated on account of a nonrespondent rate 36%, including 3.4% patients who declined to fill out the survey and 32.6% who did not visit the outpatient departments. Furthermore, those taking street drugs might seek to conceal their drug use and underreport it on the questionnaire. Second, dosing regimens and durations of treatment differed widely among these patients, and coanalgesics were not reported in this study. The exact data of concomitant nonopioid analgesics were not available because more than two-thirds of patients were not aware of the types of their oral nonopioid analgesics. We demonstrated more opioid effectiveness (beneficial effects of treatment for a population when delivered under real-world conditions) than opioid efficacy (beneficial effects of treatment delivered to a targeted group in a controlled trial)38 among these CNCP patients. Nevertheless, with a median duration of 57 months, long-term opioid therapy actually provided an acceptable solution for these highly selected Taiwanese CNCP patients. Third, the purpose of this study was to describe a specific CNCP population in Taiwan rather than to investigate the opioid epidemic and prescription-related mortality, which has become a serious public health issue in North America. This survey was conducted in 2010, at a time when the supportive use of chronic opioid therapy for carefully selected and monitored patients was based on the clinical guidelines issued by the American Pain Society and the American Academy of Pain Medicine in 2009.1 However, recent evidence supports a dose-dependent risk for serious harms of long-term opioid therapy,4 which should be taken into consideration for patients with high-dose opioid prescriptions.

This self-reported cross-sectional survey described the patients' perceptions of receiving long-term opioids and their concurrent adverse effects, depressive status, and aberrant behaviors among 210 highly selected and strictly surveilled CNCP outpatients in Taiwan. A subset of patients was prescribed high doses of opioids. More efforts are needed to determine ways to reduce the daily MED dose to the watchful dose of 200 mg, as 30.5% of patients in our study surpassed this cutoff.

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Acknowledgments

This work was supported by Taiwan Food and Drug Administration (DOH99-FDA-61404). We gratefully acknowledge the research assistant, Mr Cheng-Shien Yang, for questionnaire collection and data processing, and Ms Huei-Han Liou for statistical analysis.

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