Download Chronic Use of Opioid Analgesics in Non-Malignant Pain

Pain, 25 (1986) 171-186
Elsevier
in the role
results of
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171
PAl 00878
Chronic Use of Opioid Analgesics in
Non-Malignant Pain: Report of 38 Cases
}. Electrosecretarial
Russell K. Portenoy and Kathleen M. Foley
Pain Service, Department of Neurology, Memorial Sloan-Keaering Cancer Center, and Department of
Neurology, Cornell University Medical College, New York, NY 10021 (U.S.A.}
(Received 10 June 1985, accepted 28 October 1985)
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Summary
Thirty-eight patients maintained on opioid analgesics for non-malignant pain
were retrospectively evaluated to determine the indications, course, safety and
efficacy of this therapy. Oxycodone was used by 12 patients, methadone by 7, and
levorphanol by 5; others were treated with propoxyphene, meperidine, codeine,
pentazocine, or some combination of these drugs. Nineteen patients were treated for
four or more years at the time of evaluation, while 6 were maintained for more than
7 years. Two-thirds required less than 20 morphine equivalent mgj day and only 4
took more than 40 mgj day. Patients occasionally required escalation of dose
and j or hospitalization for exacerbation of pain; doses usually returned to a stable
baseline afterward. Twenty-four patients described partial but acceptable or fully
adequate relief of pain, while 14 reported inadequate relief. No patient underwent a
surgical procedure for pain management while receiving therapy. Few substantial
gains in employment or social function could be attributed to the institution of
opioid therapy. No toxicity was reported and management became a problem in
only 2 patients, both with a history of prior drug abuse. A critical review of patient
characteristics, including data from the 16 Personality Factor Questionnaire in 24
patients, the Minnesota Multiphasic Personality Inventory in 23, and detailed
psychiatric evaluation in 6, failed to disclose psychological or social variables
capable of explaining the success of long-term management. We conclude that
opioid maintenance therapy can be a safe, salutary and more humane alternative to
the options of surgery or no treatment in those patients with intractable non-malignant pain and no history of drug abuse.
Address reprint requests to Dr. K.M. Foley, Department of Neurology, Memorial Sloan-Kettering
Cancer Center, 1275 York Avenue, New York, NY 10021, U .S.A.
0304-3959/86/$03.50 «:> 1986 Elsevier Science Publishers B.V. (Biomedical Division)
172
Introduction
The opioid analgesics have long been accepted as appropriate treatment for acute
pain. Enthusiasm for chronic therapy, however, has traditionally been tempered by
the development of tolerance and physical dependence and by the often-stated risk
of psychological dependence after sustained exposure to these drugs. Despite these
factors, chronic treatment with opioids has gradually gained acceptance as the
mainstay of therapy for patients with pain due to cancer [2,7,8,16,29,43,50,51]. This
experience has led to the realization that effective long-term use is possible without
the development of abuse behaviors or significant toxicity in the majority of
patients with malignant pain [19,43,50]. Coupled with an increased understanding of
the pharmacology of pain and its complex central modulation, this knowledge has
provided the impetus to review the use of these medications in the population with
chronic non-malignant pain.
The use of the opioid analgesics is currently viewed as either problematic or
contraindicated in the management of intractable non-malignant pain [3,10,27,28,
32,40,49]. In addition to physical dependency and the risk of psychological dependence (32,40], it has been suggested that chronic therapy produces greater psychological distress, poorer outcome, and impaired cognition [27,28,30,32,49]. Reports of
legal action against physicians who prescribe these drugs to patients without cancer
have appeared and further support the belief that chronic administration of opioids
is dangerous in this population [48].
In contrast to this view, several groups have recently reported successful long-term
opioid therapy in patients with non-malignant pain [9,46,48]. Thus, a controversy
exists which has important clinical implications and relates to a more general
concern about the role of opioid drugs in medicine and society. This report
summarizes our experience with opioid maintenance therapy in a group of chronic
non-malignant pain patients and reviews the literature which frames the controversy, thus providing the inchoate evidence on which tentative conclusions and
guidelines for treatment can be based.
of the I
from th
The
several
disease
non-rna
treated
still un·
above.'
metric t
the tim
review,
Data
37 pati
Person<
The Ml
and ha~
of the 1
in the t
compri~
consist~
Scores'
scales f,
Fig. 2.
MM
maintai
of the
whom'
treated
intende
generat
Methods
Results
The patients reviewed in this survey were derived from two separate studies. In
the first, a review of cases currently under treatment at the Pain Clinic of Memorial
Sloan-Kettering Cancer Center was undertaken. This yielded 19 patients who
fulfilled the criteria of non-malignant pain syndromes treated with opioid analgesics
for at least 6 months. The charts of these patients were evaluated for demographic
information, history of substance abuse or psychiatric disturbance, medical history,
self-reported and staff-observed assessments of pain and pain relief, and formal
psychiatric interviews, if available. Clinical data on these patients were both
extensive and contemporary due to the long-term and ongoing nature of the
involvement between each patient and a Pain Service physician. These observations
were critical in evaluating the complex role of opioid maintenance therapy in the life
The
Female
and 9 c
(Table
causalg
venous
Twel
receive(
medical
drugs. 1
173
1t for acute
:mpered by
-stated risk
~spite these
.nee as the
50,51]. This
ble without
najority of
standing of
•wledge has
t!ation with
Jlematic or
[3, 10,27 ,28,
;ical depenter psychoReports of
1out cancer
1 of opioids
1llong-term
::ontroversy
Jre general
fhis report
. of chronic
:s the conlusions and
of the patient and the clinical conclusions drawn from this review derive primarily
from them.
The remainder of the cases were culled from a separate study [35] completed
several years ago in which patients with pain due to either cancer or non-malignant
disease were compared on various tests of personality. Thirty-seven patients with
non-malignant pain syndromes were evaluated in this study; of these, 24 had been
treated with opioid analgesics for at least 6 months. Five of these 24 patients were
still under active treatment and were included in the review of charts described
above. The remaining 19 patients were evaluated for their demographic and psychometric status and for the overall efficacy of therapy, which had been determined at
the time of the study; this group, combined with the 19 obtained from the chart
review, comprises the 38 patients of this review.
Data from two measures of personality were available from this earlier study of
37 patients. These included a shortened version of the Minnesota Multiphasic
Personality Inventory (MMPI) and the 16 Personality Factor Questionnaire (16PFQ).
The MMPI has been validated in large groups of normal and psychiatric patients
and has been used extensively in the evaluation of chronic pain patients [45]. Three
of the 10 scales, Hysteria, Depression and Hypochondriasis, have been most useful
in the evaluation of pain patients; these three, plus two validity scales, F and K,
comprised the shortened version of the test reported in this study. The 16PFQ [4]
consists of 187 questions which provide information on 16 basic personality traits.
Scores derived from factor analysis of the responses are converted into standardized
scales for which norms have been determined in the general population, as shown in
Fig. 2.
MMPI scores were available for 23 of the 24 patients with non-malignant pain
maintained on opioid analgesics; all 24 completed the 16PFQ. Mean scores on each
of the scales in both tests were compared to those from two other groups from
whom data were collected at the same time, 13 patients with non-malignant pain
treated without opioids and 26 with malignant pain. This comparison was not
intended to be a statistically valid case-control comparison, but rather an attempt to
generate suggestive correlations. The t test was used for all comparisons.
Results
studies. In
f Memorial
1tients who
j analgesics
emographic
ical history,
and formal
were both
:ure of the
•bservations
yin the life
The median age of the 38 patients was 52 years, with the range of 25-82 years.
Females outnumbered males by almost 2 to 1 . Nine patients had failed low backs
and 9 others had pain in other locations for which the etiology was undetermined
(Table 1). Various deafferentation syndromes, including postherpetic neuralgia,
causalgia, phantom limb pain, and central pain due to stroke, spinal cord arteriovenous malformation and syringomyelia, were represented as well.
Twelve patients were maintained on oxycodone preparations alone (Table II); 7
received methadone and 5 levorphanol. The remaining third took a variety of other
medications, including propoxyphene, meperidine, codeine, or some combination of
drugs. Half of the 38 patients had received opioid medications for 4 or more years;
174
TABLE I
TABLE III
DIAGNOSES OF PATIENTS WITH CHRONIC NON-MALIGNANT PAIN TREATED WITH
OPIOIDS (N = 38)
DURATIO
NON-MAL
Diagnosis
No. of patients
Chronic back pain
Discogenic +surgery
Traumatic
Syringomyelia
Spinal arteriovenous malformation
Chronic facial, abdominal, pelvic or extremity pain
Benign tumor resection
Postherpetic neuralgia
Thalamic pain
Phantom limb
Causalgia
Arnold-Chiari malformation with arm pain
Thoracic outlet syndrome
Arthritis
14
9
3
1
9
5
3
Duration of
<2
2-3
4-5
6-7
8-10
> 10
Unknown
2
Dose (i.m. m
<10
10-20
21-30
31-40
41-50
6 had been treated for more than 7 years (Table Ill). Information on daily opioid
intake was available in all 19 cases still under active treatment and in 14 of the 19
patients evaluated during the earlier study. For each patient, the quantity of drug
was converted into intramuscular morphine equivalents (Meq)/24 h [17]. Dosages
were relatively low, with 24 patients (73%) taking less than 21 Meqjday (Table III).
Detailed psychosocial information was available from the 19 patients currently
receiving active therapy. Twelve (63%) were married. Fifty-nine percent of those
below retirement age were employed before beginning opioid maintenance therapy;
39% held jobs while prescribed these medications. Nine patients (47%) received
disability payments.
Only 3 of these 19 patients had a history of chronic pain before their present pain
TABLE II
OPIOID DRUGS USED IN THE TREATMENT OF CHRONIC NON-MALIGNANT PAIN (N = 38)
No. of patients
Oxycodone
Methadone
Levorphanol
Methadonejoxycodone
Propoxyphene
Propoxyphenejoxycodone
Meperidine
Codeine
Pentazocine
Pentazocinejpropoxyphene
Levorphanoljcodeine
12
7
5
3
2
2
2
2
51-60
> 61
Unknown
began, in
joint pair
patients I
depressi01
toms afte:
depressior
psychotic
Six pa
maintenar
renee of
psychiatri·
features"'
was comn
apparent.
others der
Figs. 1
16PFQ W•
with nonrevealed a
in those 1
significant
the F and
of the rna
scales. Tht
175
TABLE III
'ED WITH
DURATION OF USE AND DOSE OF OPIOID PER 24 H IN PATIENTS TREATED FOR
NON-MALIGNANT PAIN (N = 38)
...
No. of patients
Duration of use (years)
<2
2-3
4-5
6-7
8-10
> 10
Unknown
7
10
6
7
3
3
2
Dose (i.m. morphine equiua/ents/24 h)
<10
10-20
21-30
31-40
41-50
51-60
> 61
ily opioid
of the 19
y of drug
. Dosages
able III).
currently
of those
:therapy;
1 received
Unknown
:sent pain
.,
IN (N= 38)
11
14
0
2
2
1
3
5
began, including individuals with severe migraine, ulcerative colitis and chronic
joint pain due to hemarthrosis in a patient with hemophilia. Similarly, only 3
patients had any psychiatric history, two with bipolar disease and one with
depression. A greater number, however, developed significant psychological symptoms after their pain began. These included 10 patients who described periods of
depression, usually with sleep disturbances, and 2 patients who had episodes of
psychotic behavior.
Six patients underwent formal psychiatric interviews while receiving opioid
maintenance therapy. These patients are mentioned only to emphasize the occurrence of notable psychopathology in a subgroup of this population. In 4 cases,
psychiatric diagnoses were rendered. A diagnosis of anxiety reaction with depressive
features was given to the patient described in the case report which follows and it
was commented that 'tremendous functional overlay to any organic pathology' was
apparent. Two patients received the diagnosis of manic-depressive psychosis and 2
others depression.
Figs. 1 and 2 illustrate the results of the earlier study, in which the MMPI and
16PFQ were given to 24 non-malignant pain patients maintained on opioids, 13
with non-malignant pain treated otherwise, and 26 with cancer pain. The MMPI
revealed a trend in all groups toward elevated scores on all 3 clinical scales, greatest
in those with non-malignant pain maintained on opioids. These patients scored
significantly higher than non-malignant pain patients treated without these drugs on
the F and Depression scales; their scores were also significantly greater than those
of the malignant pain patients on the Hysteria, Depression and Hypochondriasis
scales. The 16PFQ, however, demonstrated no significant differences.
176
AVERAGE MMPI SCORES
90
***
80
Qj
50
(/)
70
1
60
"0
Q)
,!:j
50
u
c
40
(/)
30
::.,
~
~Normal
[ Range
~----------------J
20
._NON-MALIGNANT PAIN-OPIATES
10
.____.NON-MALIGNANT PAIN-NO OPIATES
o-o MALIGNANT PAIN
F
K
HS
D
HY
Fig. 1. Results of the MMPI in 3 groups of patients with chronic pain. • Non-malignant pain patients
treated with opioids and non-malignant pain patients not receiving opioids significantly different at
P < 0.05. **Non-malignant pain patients treated with opioids and cancer pain patients significantly
different at P < 0.05.
AVERAGE 16PF SCORES
There v.
opioids ( e.1
among the
problems.
maintenan•
intensity o
deteriorati<
without mo
ment with
dose prior
abuse. DUJ
doses of m
revealed al
characteris
prescribed
In all 3
attempts at
patients, ac
The 6 rema
however, d,
worsening
earlier psyc
episodic se·
the 38 (639.
10
9
(!)
'-
0
()
(J)
7
'0
6
5
<0
4
'0
(!)
N
'-
'0
c
<0
05
Case repor1
8
3
2
..._.NON-MALIGNANT PAIN-OPIATES
...,____..NON-MALIGNANT PAIN-NO OPIATES
:>-o MALIGNANT PAIN
Fig. 2. Results of the 16PFQ m 3 groups of patients with chronic pain. There were no significant
differences between groups.
The typi
relatively st
escalation <
mg case reJ=
A 25-ye1
tenderness .
morphine e
biopsy, was
severe desp
anterolaten
discontinue
buttock an
comprehem
not explain
escalated tc
tapered to
later, pain s
177
pain patients
y different at
s significantly
There were no episodes of clinically significant adverse effects from the use of
opioids (e.g., acute overdose, respiratory depression, excessive sedation, myoclonus)
among the 19 patients reviewed in detail. Only 2 patients posed management
problems. The first had a history of psychosis and polysubstance abuse. Opioid
maintenance therapy was initiated for the treatment of a central pain syndrome, the
intensity of which varied with emotional state. During a period of psychological
deterioration ultimately requiring hospitalization, opioid intake was rapidly increased
without medical approval. Improved psychological function returned after treatment with psychotropic drugs and opioids were tapered to less than one-third the
dose prior to the episode. The second patient had a known history of oxycodone
abuse. During opioid maintenance therapy, the patient appeared to require high
doses of methadone for pain relief. After several months, a plasma methadone level
revealed almost no circulating drug, confirming drug diversion or hoarding. Patient
characteristics other than prior drug abuse, including adequacy of pain relief on the
prescribed drug, did not predict problems in managing opioid maintenance therapy.
In all 38 patients, opioid maintenance therapy was begun after many failed
attempts at analgesia by other means, both medical and surgical. Of the 19 active
patients, adequate pain relief was described by 7 (37%) and partial relief by 6 (32%).
The 6 remaining patients continued to have at least episodic severe pain. Even they,
however, described some degree of intermittent pain relief and in every case feared
worsening pain if analgesics were withdrawn. Of the 19 patients evaluated in the
earlier psychometric study, 4 (21%) had adequate and 7 (37%) partial relief of pain ;
episodic severe pain persisted in 8. In sum, comfort was notably enhanced in 24 of
the 38 (63%) patients surveyed.
Case report
no significant
The typical course of opioid use in patients maintained for years was marked by
relatively stable doses punctuated by exacerbations of pain often requiring transient
escalation of dose and/or hospitalization. This pattern is illustrated by the following case report (Fig. 3).
A 25-year-old man developed severe left calf pain associated with swelling and
tenderness. He was admitted to hospital in June 1975, taking approximately 28
morphine equivalent mg/ 24 h for pain. An extensive evaluation, including muscle
biopsy, was performed and no diagnosis was made. During this time, pain remained
severe despite escalating doses of medication. In July 1975, he underwent an open
anterolateral cordotomy and had complete eradication of his pain. Opioids were
discontinued and he was pain-free for several months. After this period, severe left
buttock and leg pain began. This progressed and he was hospitalized again. A
comprehensive evaluation revealed only a benign-appearing bony lesion which could
not explain the nature of his pain. Opioid therapy was reinstituted and doses were
escalated to 90 Meq/24 h before the pain stabilized. While in hospital, the dose was
tapered to a baseline level equivalent to 20 mg of morphine/day. Several months
later, pain still refractory, he underwent a biopsy of the lesion found previously, the
178
OPIATE DRUG USE IN A PATIENT WITH NON-MALIGNANT PAIN
160
~
"'"
150
f
1
~
who chr01
ment pro~
significan
Thew
against or
Hosptla/ Admtssion
N
ri-
100
E
[3,10,27,2~
c:"'
In
~
~
5
0'
w
c
.c."'
c.
0
::.
::.
~
therapy, e
conflict ar
challengin
a.
0
<ii
50
40
30
20
10
Time
Fig. 3. Fluctuations in medication dose over 11 years in a pa tient on opioid maintenance therapy for
chronic non-malignant pain. See text for case history.
results of which confirmed an osteoid osteoma. The pain associated with the
procedure was treated with a rapid increase in the dose of opioid medication; this
was again tapered to baseline in hospitaL More than a year later, during which time
he was maintained on stable baseline doses, his pain flared again. Doses of opioids
were increased and again he was hospitalized. The pain subsided gradually, allowing
return to pre-hospitalization doses. These were maintained without difficulty for
more than 3 years. A transient exacerbation in January 1981 was again treated with
admission to hospital and temporary dose escalation. Since that time, maintenance
doses have remained at baseline and he has returned to work. During all periods of
stable maintenance doses, pain relief was often incomplete but manageable, allowing him to be comfortable much of the time and function within his home and
family, even when employment was unattainable.
Discussion
This survey suggests that opioid maintenance therapy initiated for the treatment
of chronic non-malignant pain can be safely and often effectively continued for long
periods of time. This conclusion corroborates the findings of 3 other studies. Taub
[46] described 313 personally treated patients with refractory pain who were
maintained on opioid analgesics for up to 6 years. Only 13 presented serious
management problems, all of whom had prior histories of substance abuse. Escalation of dose and toxicity were not encountered and all patients appeared to benefit
from the therapy. Tennant and Uelman [48] reported 22 patients who had been
maintained on opioids after failing treatment at pain clinics. Two-thirds returned to
work and all reduced medical visits. Finally, France et aL (9] described 16 patients
"'
~
ll'
Adverse e)
No clin
surveyed,
reported i
or non-m
methadon
however,
physiologi
ations, at
by the apr
the metha
of other b
majority o
opioid use
changes, i
function . 1
[22]. Prog
patients in
organ-spe<
It has
neuropsyc
cation dq
relevance '
however, :
sedative/ f.
methadont
com pari so
benzodiazt
former gn
physiologic
contribute:
Efficacy
The effi
tives. All r
other mea
179
who chronically received low dose opioids as part of a comprehensive pain management program. Patient function was improved and neither side effects nor clinically
significant tolerance developed.
The results of these reports stand in sharp contrast to the emphatic prohibition
against opioid use in chronic pain patients found repeatedly in the medical literature
[3,10,27,28,32,40,49]. A consideration of several issues, including adverse effects of
therapy, efficacy and the risk of substance abuse, is the initial step in resolving this
conflict and developing guidelines for the pharmacologic management of these often
challenging patients.
Adverse effects
therapy for
with the
3.tion; this
vhich time
of opioids
t, allowing
ficulty for
eated with
iintenance
periods of
ble, allowhome and
treatment
:d for long
dies. Taub
who were
ed serious
se. Escalato benefit
had been
eturned to
.6 patients
No clinically significant adverse effects of opioid use occurred in the 19 patients
surveyed, despite years of therapy in some. This finding has been previously
reported in patients receiving chronic opioid therapy for pain due to cancer [19,50]
or non-malignant causes [9,46] and in patients maintained for many years on
methadone for the treatment of opioid abuse [6,21,22]. Only the latter group,
however, has been assessed for the possibility of clinically inapparent long-term
physiological or neuropsychological effects of opioid therapy. Physiological alterations, at least on the level of the opioid receptor, undoubtedly occur, as indicated
by the appearance of physical dependence after repeated exposure to these drugs. In
the methadone maintenance population, extensive studies have suggested a variety
of other biochemical and hormonal effects, most of which appear transiently in the
majority of patients [21,22]. These have included such well-known complications of
opioid use as constipation and increased sweating, as well as other, lesser known
changes, including increased levels of serum albumin and alterations in endocrine
function. None of these changes has ever been correlated with symptomatic disease
[22]. Progressive hepatic dysfunction does not occur in methadone maintenance
patients in the absence of viral hepatitis or ethanol abuse [21-23] and other serious
organ-specific toxicity has not been described:
It has been reported that detailed psychometric assessment can discern mild
neuropsychological and personality disturbances in patients with prescription medication dependency [26,30] and in those on methadone maintenance [12,13]. The
relevance of these reports to non-addicts maintained on opioids alone is doubtful,
however, since no attempt was made to control for prior or concurrent use of
sedative/hypnotic drugs or such factors as prior head trauma. Other studies in the
methadone maintenance population [24] have not confirmed these findings and a
comparison [15] of pain patients treated with opioids alone with those using only
benzodiazepine drugs found significantly less neuropsychological disturbance in the
former group. The bulk of evidence at this time, both neuropsychologic and
physiologic, supports the view that chronic opioid therapy neither causes nor
contributes to clinically significant disease [14].
Efficacy
The efficacy of opioid maintenance therapy can be viewed from several perspectives. All patients were begun on therapy after years of inadequate management by
other means, both medical and surgical. On opioids, adequate pain relief was
180
reported by 11 patients (29%) and partial relief by 13 (34%), a remarkably positive
response in this population. No patient underwent a surgical procedure for pain
while on therapy. Of the 19 patients still in active therapy, in whom the reliability of
reported efficacy was confirmed by repeated observation, 13 described partial to
adequate pain relief. Nonetheless, few patients had dramatic improvement in
employment status or family relationships attributable to the institution of treatment. Furthermore, psychological distress, assessed clinically and through psychometric testing, was neither markedly ameliorated nor exacerbated. Unfortunately,
other important indications of outcome, such as unscheduled physician visits,
activity level and proportion of time spent in bed, cannot be determined from this
review. These data suggest that opioid maintenance therapy can provide acceptable,
though often incomplete, analgesia for a significant group of refractory pain
patients, but is no panacea for the profound functional impairment commonly
occurring in this population.
The efficacy of opioid maintenance therapy did not vary systematically with any
of the demographic or psychosocial factors evaluated in the present survey. Specifically, successful therapy was not dependent on stable family life, continued employment, a known etiology of the pain or psychological intactness. The results of the
MMPI suggest that patients receiving therapy often have greater personality disturbances than their counterparts treated in other ways. Further study is needed to
determine whether this relates to an effect of therapy, premorbid personality
disorders, andj or severity of pain. It is likely in any case that psychological health is
not prerequisite to the successful management of long-term opioid therapy, nor once
started, does treatment ensure return of normal psychological function .
As reported in prior surveys of opioid maintenance therapy in non-malignant
pain [9,46], the need for escalating doses of drug did not compromise the success of
treatment in the present series. Though no attempt was made to directly assess the
development of tolerance to the analgesic effects of the opioids, the stability of the
maintenance dosage over the years and the relatively low doses used by these
patients indicate that it rarely becomes a clinically relevant issue. This stability of
dose in the absence of progression of disease has also been reported in the cancer
population [19,51].
All patients reported in the present series received long-term and intensive
treatment from a single physician who took primary responsibility for the overall
management of the patient's medical problems, as well as pain therapies. Such a
pattern of comprehensive care is also implied in the other reports of opioid
maintenance therapy mentioned above [9,46,48]. It must be recognized, therefore,
that the efficacy of this therapy and its successful management may relate as much
to the quality of the personal relationship between physician and patient as to the
characteristics of the patient, drug, or dosing regimen. This is an alternative
hypothesis for the positive results reported in this and other studies which has not
been directly assessed. The likelihood that the intensive involvement of a single
physician does impact favorably on the outcome of opioid maintenance therapy
suggests that guidelines for management should include this element, as discussed
below.
The SUl
chronic n.
patients v
negative "
this contr
which ass
centers wl
treatment
[14]. A cr
efficacy a
opioid ab1
Thougt
therapy in
survey of
abusing p1
analysis[~
[49] comr
taking eitl
found a g
groups ar
those taki
The co
ambiguitit
those pati•
relevance
just as th<
causation.
operation~
therapy, b
A recent c
ological f
percentage
to study.
successful
opioid the
not be re
assessmen
One stt
Forty-two
divided ir
group givt
of adjuvar
pain in th
the detoxi
maintenar
181
ly positive
~ for pain
liability of
partial to
;ement in
1 of treat,h psycho>rtunately,
ian visits,
from this
.cceptable,
:tory pain
:ommonly
{with any
y. Specifid employJlts of the
nality disneeded to
1ersonality
tl health is
, nor once
malignant
success of
assess the
lity of the
by these
tability of
the cancer
intensive
he overall
~s. Such a
of opioid
therefore,
e as much
: as to the
tlternative
;h has not
f a single
:e therapy
discussed
..
The suggestion from this study and previous surveys that long-term opioid use in
chronic non-malignant pain patients can provide at least some analgesia in most
patients without significant toxicity or difficulties in management contradicts the
negative view of this therapeutic approach held by most practitioners. Support for
this contrary perspective is often adduced from two types of survey data, those
which assess the outcome of patients admitted for treatment to specialized pain
centers where substitution-detoxification and behavioral techniques are used in the
treatment of chronic pain and those which evaluate the behavior of narcotic addicts
[14]. A critical review of this literature is necessary to further address the issue of
efficacy and to assess the most controversial aspect of this treatment, the risk of
opioid abuse .
Though a recent report described the integrated use of opioid maintenance
therapy in a pain clinic [9], most studies from these settings reject this approach. A
survey of patients treated at a pain clinic who were either dependent upon or
abusing prescription drugs reported a low rate of successful outcome [28]; a separate
analysis [27] of the subgroup taking oxycodone arrived at a like conclusion. A study
[49] comparing chronic pain patients taking no addicting medications to those
taking either opioids alone or opioids in combination with sedative/hypnotic drugs
found a greater number of prior hospitalizations and operations in the latter two
groups and significantly more physical impairment and MMPI abnormalities in
those taking both types of medications.
The conclusions of these studies must be interpreted cautiously in light of the
ambiguities inherent in their data. For example, studies which do not distinguish
those patients taking opioids from those using combinations of drugs may have little
relevance to the efficacy of opioid maintenance therapy. In addition, all findings,
just as those of the present survey, are correlative and do not address the issue of
causation. It is plausible, for example, that a history of multiple pain-related
operations in those treated with opioids reflects not an adverse effect of drug
therapy, but rather the treatment finally given patients who fail multiple procedures.
A recent critique of outcome studies from pain clinics [1] found significant methodological flaws in most. Nearly all involved questionnaire surveys with limited
percentages of response and outcome measures which have varied widely from study
to study. Furthermore, many of these studies use detoxification as a criterion of
successful therapy and cannot therefore fairly assess the effectiveness of chronic
opioid therapy. Finally, patients who choose the pain clinic treatment approach may
not be representative of all those with chronic pain, further complicating the
assessment of drug therapy in this population.
One study has attempted to evaluate different treatment approaches directly [47].
Forty-two patients seeking treatment for prescription opioid dependence were
divided into a group treated by detoxification followed by psychotherapy and a
group given maintenance with either propoxyphene or methadone. Despite a variety
of adjuvant treatments for pain, drug withdrawal produced significant recurrence of
pain in the detoxified group, leading to high attrition. At 3 months, all patients in
the detoxified group had left treatment, while this occurred in only 14% of those on
maintenance therapy. After 6 months, the preferred outcome of opioid withdrawal
182
was accomplished by 2 patients (9.5%) originally detoxified and 4 (19%) of those
initially maintained, a significant difference. Though pain relief and psychosocial
function were not evaluated and the small sample was self-selected for the desired
goal of withdrawal, this study does suggest that pain reemergence may become an
insuperable barrier to detoxification and that opioid maintenance therapy may
ultimately be a more successful approach whether the goals are detoxification or
pain relief alone. Comparative outcome studies between long-term opioid treatment
and other forms of therapy for chronic non-malignant pain are sorely needed.
Risk of opioid abuse
The fear of psychological dependence to prescription drugs generates enormous
anxiety among health care providers, patients and families and is perhaps the major
limitation to wider use. This issue is remarkably complex and cannot of course be
resolved by this small survey of patients. Nonetheless, an attempt should be made to
scrutinize this risk with the same objectivity as other potential outcomes of opioid
maintenance therapy.
The first step in this process is accurate definition [18]. Though the term,
'addiction,' is commonly discussed in terms of tolerance and physical dependence,
newer data suggest that it is a concept apart from these (4,14,25,33,41]. Tolerance is
the diminution of effect over time from the same dose of drug, while physical
dependence is defined by the appearance of an abstinence syndrome on abrupt
withdrawal of the drug or administration of an antagonist. These are physiological
responses related to the pharmacological properties of the drug. The label of
'addiction' should be replaced by the term, 'psychological dependence' (18], and
refers to a set of aberrant behaviors marked by drug craving, efforts to secure its
supply, interference with physical health or psychosocial function, and recidivism
after detoxification .
As amply demonstrated in patients with chronic cancer pain, neither tolerance
nor physical dependence necessarily pose difficulties in management (7, 19]. Clinically significant tolerance did not complicate treatment in this, or other (9,46],
surveys of patients receiving opioid maintenance therapy. Physical dependence may
occur in patients on chronic opioid therapy for pain, but this has never been directly
assessed. In post-addicts, both acute and protracted withdrawal syndromes have
been described after abrupt discontinuation of treatment [25,34,41], but this occurred at drug doses far above those reported in this ahd other surveys of pain
patients. Though the impact of protracted withdrawal has not been evaluated in
patients receiving opioids for medical indications, it is clear that acute withdrawal
can be obviated by the avoidance of antagonists and dosage taper prior to
discontinuation.
Support for the view that a substantial risk of opioid abuse exists in medical
patients treated for painful disease derives primarily from several older surveys of
the addict population which have influenced much of the standard teaching in this
area. Kolb [20] reported that 9% of addicts began as naive patients treated for pain.
A related study [37] found that less than 4% of addicts had this history. In a
particularly influential survey, Rayport [39] reported that 27% of white male addicts
and 1.2%
extremely 1
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183
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and 1.2% of black male addicts began opioid abuse as medical patients. The
extremely high recidivism rate after detoxification in the general population of
opioid abusers [44,52] has been viewed as a further indication of the risks in
instituting chronic opioid therapy for non-malignant painful disease.
These studies, in which addicts are evaluated for a history of medical disease,
suggest a certain inevitability to the occurrence of psychological dependence in a
significant group of patients begun on opioids. A different view evolves, however, if
medical patients as a group are evaluated for the development of opioid abuse.
Porter and Jick [38] reported that abu se occurred in only 4 of 11,882 patients
without a history of drug dependence who were treated with opioids in hospital. In
only one instance was this abuse considered major. A survey of analgesic use in
units specializing in burn pain failed to reveal a single case of iatrogenic addiction
in over 10,000 patients without prior opioid abuse who received these medications
while hospitalized [36]. A review [31] of 2369 patients with chronic headache
uncovered 3 abusing opioids, including 2 taking codeine and 1 propoxyphene. These
studies do not support the view that opioids begun for legitimate medical purposes
are used inappropriately by a significant proportion of patients.
Other studies have questioned the risk of recidivism in individuals without prior
substance abuse who begin the use of opioids. The vast majority of soldiers who
abused these drugs in Vietnam were able to abruptly cease drug use with an
extremely low risk of readdiction on return to the United States [42]. Some of these
soldiers became occasional opioid users, a phenomenon which has been well
described [11] and further contradicts the inevitability of abuse behaviors in those
chronically exposed to opioids.
These data have suggested to some a parallel between opioid abuse and alcoholism [33]. For reasons which remain obscure and probably involve an interaction of physiological and psychological factors, most people who drink do not
become alcoholic. It is likely, given the data available, that most patients exposed to
opioids do not become drug abusers. Further experience is needed to evaluate this
hypothesis.
Guidelines
Opioid maintenance therapy should be considered only after all reasonable
attempts at pain control have failed and persistent pain is the major impediment to
improved function. Though functional improvement is clearly the preferred outcome of such therapy, it should be recognized that amelioration of pain with
relatively few associated psychological or social achievements is the more common
result. Improved function, however, should always be pursued during opioid maintenance therapy through the concurrent use of ancillary cognitive/ behavioral and
physical therapies.
The committed involvement of a single physician who will evaluate ongoing
medical and psychological problems, as well as pain-related issues, should be
available before institution of opioid maintenance therapy is considered. The care of
the patient with chronic non-malignant pain is often challenging and the physician
who is the focal point of pain management services must be willing to cope with the
184
vagaries of the underlying pain complaints and the patient's fluctuating perceptions
of the treatments offered, including opioids. Since many patients with non-malignant pain can achieve only partial relief from opioid drugs, while others obtain
none, the physician must be able to make the clinical judgment that higher doses
will not be salutary or the treatment should be stopped altogether. These decisions
are difficult to implement in the setting of persistent pain complaints. They are
aided immeasurably by a clear historical understanding of the patient's problems
and an ongoing relationship from which the patient can derive support and the
certainty that decisions are made in his or her best interest.
The appropriate management of opioid maintenance requires that the patient
gives fully informed consent. Tennant and Uelman [48] have recommended that
formal written consent be obtained or a detailed notation made in the patient's
chart which documents that the patient has failed non-narcotic therapy and enters
knowingly into a trial of opioid maintenance. They suggest that the consent
discussion includes the risks of using alcohol or other drugs while taking opioids,
the likelihood that a newborn will be physically dependent on opioids if these drugs
are taken by a female patient during pregnancy, and the possibility, which the
current data cannot refute absolutely, that psychological dependence to opioids can
occur and may last a lifetime.
After a period, usually several weeks, during which doses are titrated to provide
at least partial relief of pain, a monthly requirement of medication should be set.
Patients should be seen at least monthly and prescriptions written for no longer
than this time. There should be some leeway in daily dose so that transient increases
in consumption can be accommodated as long as baseline is regained within the
month. If possible, a temporary increment in dose should be followed by reduced
intake, so that overall monthly requirement remains constant. If dose escalation
continues to rise over several weeks or if a rapid rise in the absence of a documented
change in disease occurs, it is recommended that the patient be hospitalized in order
to facilitate evaluation of the medication requirement and, if possible, return to
baseline doses. Most patients in the surveys of opioid maintenance therapy published thusfar have required modest doses of drug; the need for relatively high doses
must be especially scrutinized to ensure that the drug is appropriately used, and
specifically, that pain is the symptom being treated. Evidence of inappropriate use,
such as opioid intake t0 treat depression or anxiety, or of such abuse behaviors as
drug diversion or hoarding, should be pursued and managed firmly. If control
cannot be maintained, opioid therapy should be discontinued.
The present survey, as well as those cited above, provides suggestive evidence that
opioid medications can be safely and effectively prescribed to selected patients with
relatively little risk of producing the maladaptive behaviors which define opioid
abuse. Given the paucity of data, however, this course must be pursued cautiously.
Opioid maintenance therapy should be considered in refractory cases of non-malignant pain as an alternative therapy which may be more humane and provide greater
benefit at lesser risk than other approaches. Long-term prospective studies of pain
patients on opioid maintenance therapy are needed; these will better assess the
efficacy and risks of the treatment itself and may provide insight into the salient
features which predispose to and perpetuate drug abuse.
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i.
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~
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237-241
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