Download Complex regional pain syndrome

British Journal of Anaesthesia 87 (1): 99±106 (2001)
Complex regional pain syndrome
R. N. Harden
Center for Pain Studies, Rehabilitation Institute of Chicago, 1030 N. Clark Street, Suite 320, Chicago,
IL 60610, USA
Br J Anaesth 2001; 87: 99±106
Keywords: pain, complex regional pain syndrome
Since the early musings in the mid-1800s of Claude Bernard
and his French neurological colleagues on the association of
pain with the sympathetic nervous system, complex regional
pain syndrome (CRPS) has both fascinated and perplexed
practitioners. Some of the clearest and most interesting
descriptions of `causalgia' come from the American Civil
War by one of Bernard's students, Silas Weir-Mitchell. The
low-velocity, high-mass missiles used in this confrontation
(the `Minnie ball') seemed to be particularly effective in
inducing neuropathic pain associated with intense autonomic dysregulation. Weir-Mitchell's depictions are clear
and elegant, and as good as any clinical description that can
be found in this century.64 Many great minds have struggled
with the pathophysiology of what came to be called `re¯ex
sympathetic dystrophy' in the later part of the 1900s and
what has, since the Orlando consensus-based workshop of
1999, come to be called complex regional pain syndrome
(CRPS) (Table 1).37 63 85 From Leriche46 and his vicious
circles we have progressed through Livingston47 and
Sunderland88 with the turbulence theory, and ®nally to the
solid physiological information generated by the various
animal models of causalgia, especially the chronic constriction injury model of Bennett and Xie.5 Recently, the
effort to understand the syndrome has turned towards
consensus symposia. The ®rst of these concerned taxonomy,
as above.37 85 A second Dahlem-type conference was
conducted in regard to the guidelines for therapy,84 and
recently the International Association for the Study of Pain
(IASP) sponsored a symposium in Cardiff, Wales in 2000 to
discuss issues of pathophysiology and to amend the
diagnostic considerations.83
The epidemiology of the syndrome is very unclear.
Although the syndrome has traditionally been considered
rare, its `discovery' by personal injury lawyers in the
United States has caused a radical increase in the reporting
of the syndrome (at least in the USA). The current
diagnostic criteria, as set forth by the Committee of
Classi®cation of Chronic Pain of the IASP, have contributed
to the liberalization of the diagnosis (Table 1).63 This effort
was extremely important in providing standardized diagnostic criteria, and caused a vast improvement in clinical
communication and research homogeneity. It provided the
hope that results could be generalized across studies, and in
fact widespread use of these standardized criteria has helped
all these things considerably. These criteria, while being
very sensitive, greatly lack speci®city.9 21 31 The intent of
the Orlando conference in 1994 was that these criteria
should evolve on the basis of experience and empirical
testing, and that they should be subject to systematic
validation research over time.37 62 85 This has been
accomplished to some extent, and through a process of
internal and external validation the opportunity to improve
the speci®city of the bedside diagnostic criteria is
available.9 21 31 Although the original IASP criteria required
only subjective and potentially only historical signs and
symptoms, the suggestions for improving these criteria are
that some objecti®cation and observed evidence be
included. It is recommended that the diagnostic criteria be
modi®ed to include at least one symptom in each of the four
diagnostic categories derived by factor analysis: sensory
(hyperaesthesia), vasomotor (temperature and/or skin
colour asymmetry), sudomotor/oedema (reports of asymmetrical oedema in the affected limb and/or a sweating
asymmetry), and a new symptom set which was identi®ed
by factor analysis: the motor/trophic set (reports of motor
dysfunction or trophic changes).9 21 31 Our data also suggest
that the patient should display at least one quasi-objective
sign (observed by the physician) in two or more of these
categories (Table 2).9 31 This approach maintained a
sensitivity of 0.70 while increasing speci®city to 0.94.
This level of speci®city is important in research. However,
the original IASP criteria could be used if maximal clinical
sensitivity was desired. A variety of schemes in which the
clinician/researcher can virtually set the sensitivity and
speci®city, depending on the diagnostic scheme used, have
been discussed.9 31
Ó The Board of Management and Trustees of the British Journal of Anaesthesia 2001
Harden
Table 1 IASP diagnostic criteria for complex regional pain syndrome (adapted from Merskey and Bogduk).63 *Not required for diagnosis; 5±10% of patients
will not have this
1
2
3
4
The presence of an initiating noxious event or a cause of immobilization*
Continuing pain, allodynia or hyperalgesia in which the pain is disproportionate to any known inciting event
Evidence at some time of oedema, changes in skin blood ¯ow or abnormal sudomotor activity in the region of pain (can be sign or symptom)
This diagnosis is excluded by the existence of other conditions that would otherwise account for the degree of pain and dysfunction
Table 2 Proposed modi®ed research diagnostic criteria for CRPS (adapted from Bruehl and colleagues9 and Harden and colleagues31)
1
2
3
Continuing pain that is disproportionate to any inciting event
Must report at least one symptom in each of the four following categories:
Sensory: reports of hyperaesthesia
Vasomotor: reports of temperature asymmetry and/or skin colour changes and/or skin colour asymmetry
Sudomotor/oedema: reports of oedema and/or sweating changes and/or sweating asymmetry
Motor/trophic: reports of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin)
Must display at least one sign in two or more of the following categories:
Sensory: evidence of hyperalgesia (to pinprick) and/or allodynia (to light touch)
Vasomotor: evidence of temperature asymmetry and/or skin colour changes and/or asymmetry
Sudomotor/oedema: evidence of oedema and/or sweating changes and/or sweating asymmetry
Motor/trophic: evidence of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin)
Symptoms
There is great heterogeneity of symptoms endorsed by
patients with CRPS.69 It is essentially a disorder characterized by pain and dysfunction of the sympathetic nervous
system. The symptoms most frequently mentioned by
patients are spontaneous burning and stinging pain.
Although burning pain was an essential part of earlier sets
of criteria,97 it has recently been found to occur in 81.1% of
patients meeting criteria for CRPS31 (all the percentages
reported for symptoms and signs in this paper are from this
reference). Patients frequently (69%) relate hyperaesthesia
in response to the typical mechanical stimuli encountered in
their daily lives, such as clothing resting on the affected
part, or even draughts blowing on the limb. Patients may
relate extreme sensitivity to temperature changes, such as in
the environment or in bathing. In CRPS II (which is CRPS
associated with major nerve damage63), patients may often
complain of symptoms appropriate to the neuropathy, such
as brief electrical sensations or shooting pain. In this
context, they may also demonstrate an interesting presentation of hypo-aesthesia (negative symptom) in the nerve
distribution associated with electrical `shocks' and extreme
allodynia (positive symptoms). Other symptoms include
asymmetry of the colour or temperature of the affected limb;
these are the symptoms most indicative of vasomotor
autonomic disturbance (86.9% colour, 78.7% temperature).
Sudomotor symptoms can be seen with sweating asymmetry
(52.9%), either hyperhidrosis or dryness. Patients may also
endorse changes in the skin, nails or hair pattern (trophic
changes, 24.4, 21.1 and 18% respectively) and will
frequently mention that the limb swells (79.7%) and
becomes stiff. Patients frequently also speak of decreased
range of motion (80.3%) or loss of motor competence
(weakness) in the affected limb (74.6%). They will occa-
sionally notice `jumping', tremors or myoclonic action in
the affected part77 91 (about 20% each) and symptoms of
myofascial pain in the proximal joint.72
Signs and tests
The examining physician should seek evidence of altered
central processing by looking for allodynia (innocuous
stimulation that is now painful, 74%) or hyperpathia
(slightly painful stimulation that is now signi®cantly painful
and/or painful for a prolonged period). Allodynia should be
tested using light touch or brushing of the affected part to
see if this elicits pain. Temperature allodynia should be
sought. This is most easily tested using warm, cool and
ambient-temperature test-tubes of water. The test-tubes are
presented in a speci®c order on the affected part. The patient
should mentally subtract the sensation/pain of the ambient
tube from the pain associated with the cool or hot tube
(subjectively). This is most easily done by assessing pain on
a verbal Likert scale (0±10) and recording the spontaneous
report, the ambient report and the report of the effect of
temperature. These signs can be documented formally by
quantitative sensory testing.19 28 99 The patient may also
report pain on movement of the affected joints (with either
passive or active movement). Signs of trophic changes of
the skin, nails and hair patterns (19.1, 9.3 and 8.5%
respectively) should be observed and documented. Signs of
autonomic disturbance (temperature asymmetry 56.3%,
colour asymmetry 66.4%) need to be measured and
described in terms of apparent sympathetic hypofunction
(hot, red and dry) or apparent sympathetic hyperfunction
(cold, blue, pale or mottled, and sweaty).
Whether these signs accurately re¯ect activity of
the sympathetic nervous system is questionable.33
100
Complex regional pain syndrome
Thermography, or at least a spot-temperature measurement
(using a thermosensitive tape or spot-temperature device),
best documents vasomotor autonomic disturbance.10
Abnormal activity of the sudomotor side needs to be
assessed clinically using the examiner's touch (24.2%).
Dragging a smooth-handled instrument across the affected
versus the unaffected part can also give an idea of
`sweatiness' (a smooth-handled instrument will glide more
easily over a sweaty area than a dry area). Sudomotor
abnormalities can be documented by QSART (quantitative
sudomotor axon re¯ex testing).48 Decreased range of
motion (70.3%), weakness (56.1%), dystonia (14.0%) and
tremor (8.8%) can also be seen77 and myoclonic activity has
been observed occasionally.91 An interesting phenomenon
of apparent motor neglect is also observed sometimes.21 We
do not ®nd three-phase bone scans to be particularly helpful
(sometimes they are actually confusing!).45 96 However, we
often ®nd sympathetic skin-response testing helps us to
de®ne mechanisms better. In some cases the response may
be absent or abnormal in early (hot, red, dry) CRPS, but is
usually normal in later (cool, blue, sweaty) CRPS.
Treatment
A second Dahlem-type conference was held in Malibu to
generate consensus about treatment guidelines.84 All treatments were focused primarily on functional restoration; the
use of drugs, blocks and psychotherapy was reserved for
patients failing to progress in the functional algorithm
(Fig. 1). Interdisciplinary pain management techniques
emphasizing functional restoration are thought to be the
most effective therapy; they may work by resetting altered
central processing and/or normalizing the distal environment.
The principle of functional restoration is based on steady
progression from very gentle movements on an active basis
to gentle weight-bearing, such as carrying light bags in
upper-extremity syndromes or putting partial weight on the
lower extremity in gait training. This progresses to movements that involve more active load-bearing such as the
scrub-and-carry techniques of Carlson and Watson.12 95
Gradual desensitization to increasing sensory stimulus goes
along with increased function. This could include such
strategies as progressive stimulation with silk, progressing
to cloths of other textures, such as towelling, or contrast
baths that progressively broaden the temperature difference
between the two baths. It is thought that perhaps this gradual
increase in normalized sensation tends to reset the altered
central processing in the nervous system. It is important to
manage oedema, optimize the range of motion and encourage general aerobic activity throughout.84
Another basic principle of these functional restoration
guidelines is that if patients do not progress through the
steps in a reasonable time, then other interventions will be
added progressively to give the patient greater comfort or
con®dence so that they may proceed to the next level. For
Fig. 1 Steps towards functional restoration. Failure to progress in 2±4
weeks to the next step should cause consideration of more aggressive
blocks, psychotherapy and/or pharmacotherapy, depending on the
situation. Adapted from Stanton-Hicks.84
instance, if the allodynic pain is too great, a sympathetic
and/or somatic block may give the patient a window of
opportunity to begin to entertain more aggressive therapy
or, if the patient has kinesiophobia (fear of movement),16 17 57 then cognitive behavioural techniques could
be undertaken to demonstrate to the patient that movement
does not necessarily lead to entirely negative consequences.
Neural blockade, psychotherapy and drugs are reserved and
should be used only when there is failure to progress.84
Occupational therapy
The roles of occupational therapists and physiotherapists
differ in many countries. In the USA, the occupational
therapists take the lead in functional restoration, and thereby
take the lead in the team for treating CRPS.78 They begin by
initiating gentle active movements and preliminary desensitization techniques. Later, they measure and manage the
oedema (using volumetry to measure and bandaging and
lymph ¯ow massage to manage). They are also responsible
for introducing and maintaining a programme of scrubbing/
loading.12 95 The scrubbing can literally be accomplished
using a scrubbing-brush, and is usually done with the patient
on all fours, putting gradually increasing weight on the arm
as they actually scrub in circles. There are technical devices
that have been designed for this purpose, but they do not
seem to hold any particular advantage over the good old-
101
Harden
fashioned scrubbing-brush. A crucial therapeutic point of
the scrubbing/loading technique is the weight-loading of the
joints in the affected limb, which increases progressively as
the scrubbing programme continues. In the upper extremity,
the weight-loading part of the treatment continues with
small objects carried in the hand, and soon progresses to a
handled bag, which can later be loaded with heavier
weights.
The lower extremity can be treated with a customdesigned and padded strapping arrangement that attaches a
scrubbing-brush like a shoe to the foot. Loading can start in
a sitting position, but would gradually progress to standing
and putting increasing weight on the foot for brushing.
Walking is a relatively advanced loading technique but is
clearly one of the most important goals to entertain as early
as possible in the treatment of lower extremity CRPS. This
therapy may be supplemented by psychology in situations
involving post-traumatic stress disorder (PTSD), especially
in vocational situations.
Vocational rehabilitation
As the patient progresses, the therapist will begin to work
on assessing and simulating work activities. A thorough
understanding of the prior job description and requirements,
and occasionally vocational testing and targeted retraining,
are part of vocational rehabilitation. Eventually, vocational
rehabilitation can provide work capacities and targeted
work-hardening and functional capacity assessment, so that
the patient may return to gainful employment, the ultimate
functional restoration. It usually requires a methodical,
informed, experienced and organized team approach in
order to understand and successfully manage the Byzantine
social and medicolegal quagmires CRPS patients may ®nd
themselves in. This effort is best orchestrated by vocational
rehabilitation.
Physiotherapy
Physiotherapy obviously has an important roll in functional
restoration, and the activities in physiotherapy are designed
to complement those in occupational and vocational
therapy.78 Beginning with small, gentle active therapies
by the patient, the physiotherapist can help the patient begin
to extend the range of motion and ¯exibility through mostly
active, gentle activities. These must be done within the
patient's tolerance and never in an insensate situation (such
as after a block) or in CRPS type II with hypo-aesthesia.
Gradually increasing strength and ¯exibility with ultimate
return to normal use is the goal, and this is accomplished by
a series of exercises, devices (e.g. foam rubber balls
progressing to spring grip strengtheners) and mat exercises.
The physiotherapist is also actively involved in gait training
and postural correction. It is important to remember that
nearly all patients with advanced CRPS will also have
myofascial pain syndrome of the supporting joint.72 87
Aggressive treatment of myofascial pain syndrome is the
purview of the physiotherapist, and may be critical to
recovery. According to some schools of thought, the
myofascial pain syndrome must be treated effectively ®rst;
if it is treated the entire syndrome may resolve.72
Occasionally, hands-on techniques can be used effectively
to treat the myofascial pain, such as massage and myofascial
release. Desensitization techniques, such as rubbing with
silk, then cotton, then towelling or contrast baths, can be
very useful. In our experience, electrostimulation modalities
may occasionally have some use.44 Ultrasound and
diathermy therapies are less effective in our clinic.68 The
physiotherapist may co-treat with psychology to break
through PTSD and kinesophobia.16 17 42 93
Recreational therapy
Often the recreational therapist is the ®rst clinician to be
able to get the patient to move freely and with some
pleasure. In the context of restoring the patient to a pastime
or a game that they once enjoyed, it may be possible to break
through the kinesophobia and bracing that so often accompany CRPS. With assisted devices and creativity (such as
learning to bowl with the non-dominant hand, ride a bicycle
instead of run, etc.), a patient can sometimes break the ice
and ®nd enjoyment and socialization in previously lost or
new recreational activities.
Psychology
Psychology is a critical mainstay of treatment in CRPS, and
in some patients may be essential to recovery. There is a
high incidence of depression and anxiety in the
syndrome,8 49 and cognitive behavioural psychotherapy is
the most effective psychological intervention for these
diagnoses in association with chronic pain. In addition to
anxiety and depression, there is a high prevalence of posttraumatic stress disorder (PTSD) and what has been called
`kinesophobia'.8 16 17 49 PTSD is often associated with the
initial injury and can prevent full recovery because the
patient fears re-encountering the circumstances of their
injury.57 93 Kinesophobia is more an ongoing operant issue
associated with negative reinforcement when patients
perform particular movements.42 Patients ®nd that whenever they perform certain manoeuvres they have pain, which
acts as a powerful negative reinforcer for performing that
movement again. They set up operant patterns that avoid
these painful movements, and eventually this avoidance
becomes behaviourally set. It is important to demonstrate to
patients that the consequences of movement are not always
totally negative or painful, and this can be accomplished
with a combination of psychotherapy and drug or block
therapy.84 We have learned that normalized movement is
critical in the recovery of CRPS patients and a variety of
movement therapies, such as the Feldenkrais and Alexander
techniques, can be undertaken in the context of psycho-
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Complex regional pain syndrome
therapy. Family therapy can also be quite important, with
the basic approach of trying to change solicitous family
members into coaches.
Medication
There are many medications that have been reported to be
helpful in CRPS, but few that have been tested in doubleblind, randomized, controlled trials.26 At this time, a
balanced empirical approach involving observation, consideration of possible mechanisms and the use of the best
current information to treat these mechanisms, is the most
productive clinical approach. Although monotherapy is
the ideal, in practice `rational polypharmacy' is often
employed. This requires a knowledgeable guess as to the
mechanisms responsible for the condition, and then combining drugs that make sense together (i.e. an anti-in¯ammatory and a centrally acting GABAergic agent). Two basic
classes of medications should be entertained: drugs used for
prophylaxis (used daily) to manage pain and other symptoms, and abortive drugs (drugs used as rescue agents) for
crisis management.
The prophylactic drug selected will often be determined
by the presentation of the patient. For example, if a CRPS
patient is extremely depressed and/or anxious and insomniac, the clinician may choose a tricyclic antidepressant
with signi®cant analgesic, sedative and anxiolytic properties
as the drug of ®rst choice. The tricyclics are traditional in
neuropathic conditions,54 56 59 94 and seem to be partially
effective in CRPS. Good clinicians should have several
tricyclic/quadracyclic drugs in their repertoire as they have
varied side-effects that can sometimes be used to the
patient's advantage.55 56 Consider the previous example, or
consider a patient who is depressed, overweight and
hypersomnolent with psychomotor retardation. In such a
case it may be useful to select a more noradrenergic agent,
such as desipramine, which is activating and may cause
some anorexia.55 Tricyclic and tetracyclic antidepressants
have been shown to be effective in other neuropathic
conditions, such as post-herpetic neuralgia and diabetic
peripheral neuropathy.10 33 45 48 84 96 However, they have
never been studied properly in CRPS.41 Selective serotonin
reuptake inhibitors have been disappointing for CRPS in our
experience.81 82 Certain newer antidepressant agents, such
as venlafaxine and mirtazapine, show some bene®t in our
clinics.
The anti-epileptic compounds are some of the beststudied drugs in neuropathic pain,58 and currently hold
signi®cant promise in the treatment of CRPS. Gabapentin
has been studied in large randomized controlled trials in
post-herpetic neuralgia and diabetic peripheral neuropathy.3 74 The research community's attention was originally drawn to gabapentin by an anecdotal report in CRPS
(called `re¯ex sympathetic dystrophy' in that report).61 The
mechanism of action in Gabapentin may be of interest in
CRPS,13 34 but it is incompletely understood.73 It probably
works primarily by enhancing natural g-aminobutyric acid
(GABA) systems in pain modulation but may also have
some impact in suppressing excitatory amino acids, such as
glutamate.29 Other GABAergic drugs have not been tested
properly in CRPS.
Membrane-stabilizing anti-epileptic drugs such as phenytoin may have some use, particularly where there is nerve
damage or a belief that ectopic activity is involved in
generating the pain.14 53 98 Lamotrigine has been studied in
other neuropathic conditions, but randomized controlled
trials, especially in CRPS, are lacking. Carbamazepine,
which is membrane-stabilizing as well as tricyclic, has a
traditional and perhaps clinically important place in the
treatment of CRPS, but there are no speci®c randomized
controlled trials.11 76 Oxcarbazepine may be as effective as
carbamazepine but has fewer side-effects.
Non-steroidal anti-in¯ammatory drugs probably have
some role in the management of CRPS, as seen in some
other neuropathic models, particularly in cases where there
is considerable in¯ammation.15 22 35 41 66 Certain drugs in
this class may be more useful, such as ketoprofen, which has
detectable anti-bradykinin and anti-prostacyclin effects as
well as the usual anti-prostaglandin effect. COX-2 inhibitors
have not been tested in CRPS. Steroids can be particularly
useful in the early/acute phases of CRPS, again particularly
when there is signi®cant in¯ammation. A short course of
steroids may be indicated, but longer courses have a
questionable risk±bene®t ratio.41
Opioids may be useful, especially in the acute pain
scenario. However, they remain controversial in chronic
pain management.30 41 We have employed a strategy of
trying to use non-opioid medication for prophylaxis and
using opioids in crisis management. We often tie the use of
opioid therapy to increasing function, and may use an acute
or subacute opioid protocol to allow the patient to begin to
progress in non-pharmacological therapies. Issues of tolerance and long-term toxicity are unresolved as yet30 32 and
there is concern that long-term opioid use may actually elicit
allodynia and/or hyperpathia.51 NMDA receptor antagonists
(such as MK-801, ketamine and dextromethorphan) have
been considered for management of these effects (and for
CRPS), but have proved too toxic for regular human
use.18 52 65 70 89 Low-dose subcutaneous ketamine may have
a role.
Many medicines from other ®elds have proved to be
helpful, not only in the management of pain (e.g.
clonidine90) but also in the management of symptoms
associated with CRPS (e.g. nifedipine, which can control
the intense vasoconstriction sometimes associated with
chronic CRPS). Interestingly, calcitonin is one of the beststudied drugs in the management of CRPS.7 23 24
Unfortunately, the evidence is mixed and our anecdotal
experience with this compound is not particularly encouraging.
The lidocaine patch may be useful in some very local or
focal CRPS phenomena, such as patch allodynia.75 EMLA
103
Harden
(eutectic mixture of local anaesthetics) cream has been
disappointing in our clinic.2 Capsaicin has proved to be
intolerably painful early on, messy, and thereby to engender
very poor compliance, in our experience.6 25 41 67 80
While a variety of block therapies have been the
traditional ®rst line of treatment in CRPS, there is very
little scienti®c evidence to support their use.86 We view
blocks primarily as providing a pain-free period so that
patients may progress in the functional restoration algorithm, and we use them sparingly in that context. Many
blocks have been examined, and the most frequently used
are paravertebral sympathetic blocks and epidurals.86
Although it appears clinically that there is excessive
sympathetic activity in the later phases of CRPS, the
peripheral picture (cold, blue, sweaty extremity) may not
actually re¯ect what is going on in the sympathetic efferents
to the limb.33 Intravenous phentolamine has been reported
as useful both therapeutically and diagnostically1 71 but is
not useful therapeutically beyond the placebo effect in our
experience.41 92 Intravenous regional sympathetic blockade
using guanethidine27 or bretylium41 seem to be more
helpful, and have a longer-lasting effect in our patients.
The research available is less enthusiastic.36 41 The use of
any of these interventions in a frequent or chronic way has
never been justi®ed substantially in the scienti®c literature.
A short trial of a limited number of nerve blocks with very
clear goals and time limitations may be indicated ethically
and may be cost-effective if the patient fails to progress
naturally in a functional restoration effort.
Although sympathectomy has some theoretical
support,4 40 79 it has not shown any long-term bene®t in
our patients, and may have a negative impact in some
cases.4 20 50 Spinal cord stimulation is of controversial
utility and until recently had not been properly
studied.38 43 44 60 A recent randomized controlled trial
supports its value in cases where nothing else is helping.39
Implanted pumps have not been studied properly, and have
no long-term utility in our experience.
References
Conclusions
The key to the successful diagnosis of CRPS is not only to
look for and document those historical/subjective elements
that meet IASP criteria but also to search for quasi-objective
signs (examiner-witnessed). A more speci®c approach
would be to consider the research criteria proposed in
Table 2.
The key to successful treatment of CRPS is a trained,
coordinated and experienced interdisciplinary team employing a functional restoration approach (Fig. 1). Guidelines
help,84 but creativity, compassion and ¯exibility are essential. Often patients will require diligent pharmacotherapy,
blocks or intensi®ed psychotherapy if they are to make
substantial progress.
104
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