Chou et al. performed a systematic review of trials to compare efficacy and safety of
70 Although the evidence was considered to be of fair
quality, they concluded that for the treatment of musculoskeletal pain, tizanidine,
orphenadrine, carisoprodol, and cyclobenzaprine were more effective than placebo.
There were not sufficient data of good quality to determine whether metaxalone,
methocarbamol, chlorzoxazone, baclofen, or dantrolene was better than placebo for
this indication. At this time, guidelines do not recommend chronic use of muscle
relaxants for musculoskeletal pain. There is a small study that shows improvement in
myofascial pain with tizanidine, but there are no data supporting continued use of
carisoprodol or cyclobenzaprine.
88 These agents belong to a chemically diverse
family, but all work in the CNS, either in the brain or in the spinal cord. They are
categorized as either antispasmodics or antispasticity agents. The antispasmodics are
either benzodiazepines (e.g., diazepam) or nonbenzodiazepines (e.g.,
cyclobenzaprine) and are used for muscular pain and spasms associated with
peripheral musculoskeletal conditions. The antispasticity agents reduce spasticity
associated with upper motor neuron disorders such as multiple sclerosis (e.g.,
tizanidine, baclofen) (Table 55-11). Because J.P. has not experienced any
improvement in his pain with previous trials of muscle relaxants, switching to
another is not likely to yield any improvement in his symptoms, though tizanidine has
CASE 55-3, QUESTION 5: J.P. returns after 3 months with a small improvement in his back pain. He is
J.P. is getting about 30% improvement with oxycodone/acetaminophen, which is a good response for any
Drug Dose Adverse Effects Monitoring/Comments
Cyclobenzaprine 5 mg TID, titrate to 10 mg
Metaxalone 300 mg TID–QID GI upset, nausea, vomiting,
Methocarbamol 1,500 mg TID, or 1,000
Orphenadrine citrate 100 mg BID Syncope, nausea, vomiting,
Chlorzoxazone 500–750 mg TID–QID Lightheadedness,
Carisoprodol 250–350 mg TID and at
Tizanidine 4 mg TID, titrate to max
Baclofen 10 mg TID, titrate to max
Diazepam 2 mg TID, titrate to max
Although opioids are not recommended for chronic low back pain, J.P. has noted
an improvement in pain and function.
It would be reasonable to consider continuing
his analgesic combination. There are several analgesic options available for patients
who are unable to tolerate or ingest solid oral dosage forms (tablets and capsules). It
is common for patients with feeding tubes and patients who have maxillofacial
surgery to use alternative dosage forms such as oral liquids, topicals, or transdermal
products (Table 55-12). J.P. has asked about a pain patch. It is likely that he is
referring to either a fentanyl transdermal system or a buprenorphine patch. These
agents offer extended delivery options, but are often not cost-effective; therefore, a
pain patch may not be the best choice for J.P. Because he is able to take oral
medications, it would be most reasonable to rotate to an oral opioid that offers a
longer duration of action. When considering product rotation for J.P., it is important
to consider drug formulation and availability, route of administration, drug
interactions, adverse effects, and cost. The oxycodone/acetaminophen product that he
is currently using is not providing an adequate duration of analgesia. He may need to
use an extended-release/long-acting (ER/LA) opioid to achieve sustained analgesia.
There are many ER/LA opioid formulations available including morphine (tablets,
capsules), oxycodone (tablets), hydromorphone (capsules), methadone (tablets),
oxymorphone (tablets), hydrocodone (capsules, tablets), buprenorphine (patch,
oxycodone/acetaminophen, converting to a extended-release formulation of
oxycodone seems the most logical choice. J.P. is currently taking eight 5-mg tablets
of oxycodone daily (40 mg total per day). This may be directly converted to ER
oxycodone 20 mg orally twice daily, with elimination of the short-acting product. If
he continues to have nausea after his doses of oxycodone, he may need to rotate to
another opioid or use a nonoral route of administration, an antiemetic, or a nonopioid
J.P. has been using several different analgesics for his pain, including an NSAID,
an anticonvulsant, an antidepressant, and an opioid. These agents will offer
pharmacologic activity at several points in the pain pathway (Fig. 55-2) and offer
90,91 However, multimodal therapy also carries the risk of
additive adverse effects and possible drug interactions. For example, the
anticonvulsant and the opioid may cause additive sedation. The balance between
adverse effects and analgesia must be considered with any changes in drug therapy.
hyperkalemia or acute renal blood ow compromise. A nonacetylated salicylate such
as salsalate or diflunisal may offer analgesia with a lower risk potential and fewer
adverse effects and drug interactions. They have minimal effects on prostaglandin
Analgesics for Patients Who Cannot Take Solid Oral Dosage Forms
Acetaminophen (elixir, liquid, solution, suspension, syrup)
Hydrocodone/acetaminophen (elixir, solution)
Lamotrigine (disintegrating tablet)
Fentanyl (mucous membrane lozenge, buccal tablet, buccal film, sublingual)
Buprenorphine (sublingual tablet, buccal film)
Local anesthetics (ointment, gel, cream)
How should J.P.’s therapy be monitored?
Clinicians must assess each part of J.P.’s care plan, both the positive aspects and
the negative aspects. Is J.P. meeting his goals on his personal care plan? Is he getting
more sleep? Is he more physically active? Is he managing his stressors better? Is his
pain improved? There are several monitoring tools that may be used routinely to
record long-term progress. The “5 A’s” of monitoring therapy are often used:
analgesia, activities of daily living, adverse effects, affect, and potential aberrant
In addition to monitoring for efficacy, assessing for adverse effects of his
medication is critical. Gabapentin may cause sedation, dizziness, edema, and
cognitive impairment of short-term memory, concentration, and word-finding.
Meloxicam, an NSAID, may cause GI upset or ulceration, so he should be advised to
watch for black, tarry, sticky stools or any sign of internal bleeding. He may
experience easy bruising and bleeding related to the platelet inhibitory effects of
NSAIDs and should have his serum creatinine and potassium checked regularly to
monitor for NSAID-induced renal toxicity. His blood pressure should also be
monitored regularly because this has been elevated in the past. Oxycodone may cause
constipation, sedation, dry mouth, and urinary retention. If he is using the opioid
regularly, he should be advised to also use a bowel regimen with a stool softener,
osmotic laxative, or a motility agent. Additionally, if he is using the opioid for an
extended period of time, he may need to have his testosterone levels checked and
bone density testing done periodically to monitor for hypogonadism and
osteoporosis, which are associated with chronic opioid therapy. Amitriptyline may
cause additive sedation, constipation, and urinary retention. He is unlikely to have
problems with orthostatic hypotension, but this is common in older patients.
CASE 55-3, QUESTION 7: What nonpharmacologic therapies may be beneficial for J.P.’s pain?
Koes et al. found that most guidelines recommend a supervised exercise program,
cognitive behavioral therapy, and short-term pharmacologic therapy.
recommends that epidural steroid injections and possibly surgery may be considered
in patients with persistent radicular low back pain. Because J.P. has radicular pain
into his legs and he has tried first-line therapies, he may be a candidate for an
epidural steroid injection. This will only offer temporary relief, at best, but may
provide him enough relief to participate more in physical rehabilitation. Studies
show mixed results with both injections and surgery, so J.P. must be part of the
In the past, patients were advised to use bed rest for acute back pain; it is now
recommended that patients remain physically active. This has been shown to improve
pain and function at 3 to 4 weeks compared with bed rest.
recommended for chronic back pain. J.P. still has limited physical activity and was
noted to be deconditioned. Inactivity can increase muscular pain. A referral for
physical rehabilitation is a key component of management, specifically a supervised
exercise regimen. There is no difference in benefit among different forms of exercise,
so J.P. and his therapist may build a program that best fits his interests and needs.
Physical rehabilitation also may include stretching and strengthening, but these are
not effective unless used as part of a comprehensive exercise program. Other
modalities such as cold packs to reduce inflammation in the acute phase of an injury
and heat to relax muscles may be used, but there is no evidence supporting either of
these therapies. Spine manipulation and low back corsets have shown some efficacy,
but other physical modalities such as massage, ultrasound, traction, injections,
acupuncture, or shoe lifts have not been shown to be effective.
he has more pain after he starts an exercise regimen, because his muscles get
reconditioned. J.P. should be encouraged and given assurances that physical activity
that is at an appropriate level for his needs may cause him to hurt but will not harm
him. He can also learn how to pace his activities so he does not overdo it with yard
work as he has done in the past.
Cognitive behavioral therapy (CBT) and mindfulness-based stress reduction
(MBSR) have been shown to improve back pain and functional limitations.
health care is an essential component of multidisciplinary pain management. CBT
perception of pain and expectations, focusing on mood, catastrophizing, negative
thinking, and poor coping skills. MBSR focuses on increasing awareness and
acceptance of moment-to-moment experiences including physical discomfort and
difficult emotions. After J.P.’s depression is addressed, he can work with a therapist
on coping skills and how to use self-regulation and manage stressors.
NEUROPATHIC PAIN AND POSTHERPETIC
Pain may be centrally or peripherally mediated. Peripheral sensory neuropathy
usually involves injury or insult to peripheral nerves, like postherpetic neuralgia
(PHN), which affects spinal nerve dermatomes. The pain tends to be fairly localized,
either regionally or along an associated dermatome. Central pain syndromes originate
from injury to the CNS or alteration in central pain processing, as occurs with
neuroplasticity. Central pain presents with a larger affected area, up to and including
unilateral, head-to-toe pain that may be seen after a stroke.
Herpes zoster occurs in 500,000 Americans each year, and approximately 20% of
these patients experience PHN.
96,97 Evidence-based guidelines for treating
neuropathic pain have been sponsored by several international organizations in the
20 Most studies have been conducted in PHN and diabetic
peripheral neuropathy (DPN), because these are the most common neuropathic pain
conditions. Some types of neuropathic pain (e.g., spinal cord injury and human
immunodeficiency virus neuropathy) have been quite resistant to pharmacologic
therapy. Studies to date have shown only partial relief of neuropathic pain regardless
of pharmacologic treatment. Doses, adverse effects, and monitoring for these agents
First-line treatments for neuropathic pain include SNRI antidepressants such as
TCAs, venlafaxine, and duloxetine. These antidepressants demonstrate effective pain
relief, even in patients without concurrent depression. The TCAs are inexpensive and
easily administered once daily; however, they have significant anticholinergic
adverse effects, such as dry mouth and constipation that many patients do not tolerate.
The secondary amine antidepressants, like nortriptyline, have fewer anticholinergic
adverse effects than the parent compound amitriptyline and are similarly effective.
TCAs are known to cause orthostatic hypotension and urinary retention in elderly
patients and may cause cardiac arrhythmias with higher doses. Venlafaxine functions
as an SSRI at low doses and needs to be titrated by 37.5- or 75-mg increments each
week to reach a target dose of at least 200 mg daily. At this dose, venlafaxine offers
SNRI activity. However, at higher doses (>225 mg/day), increases in blood pressure
and heart rate caused by increased NE activity may cause patients to stop therapy.
Duloxetine has shown efficacy in treating neuropathic pain with doses of 60 to 120
98 Cardiac rhythm, blood pressure, and pulse rate do not seem to be affected
by duloxetine. The most common adverse effect with duloxetine is nausea on
initiation and sweating. The dose of duloxetine is titrated up over 2 weeks to
minimize the nausea. Duloxetine is contraindicated in patients with liver disease or
those who drink alcohol, because there have been reports of liver failure with this
Anticonvulsants that bind to voltage-gated calcium channels are also considered
first-line therapies for C fiber-related neuropathic pain (such as DPN and PHN),
allodynia, and nonpainful dysesthesias (i.e., abnormal sensations). They have also
been very helpful in reducing central sensitization by preventing the release of
glutamate and blocking glutamate receptors. Gabapentin and pregabalin
(gabapentinoids), both voltage-gated calcium-channel blockers, have shown efficacy
and are FDA-approved for treating neuropathic pain, including PHN and DPN.
These agents must be taken 2 or 3 times daily and may cause dizziness, somnolence,
peripheral edema, and cognitive problems. The somnolence is usually managed with
a slow titration, but these combined effects may be significant in elderly patients.
Although neither agent has many drug interactions, the doses must be reduced for
renal insufficiency, because they are mostly renally eliminated.
Anticonvulsants that block sodium channels, such as carbamazepine,
Carbamazepine is an older agent that requires routine monitoring of complete blood
counts (CBCs) for blood dyscrasias, liver transaminases for possible hepatitis, and
serum sodium for possible syndrome of inappropriate antidiuretic hormone
(SIADH)-induced hyponatremia. It is also a strong cytochrome P-450 enzyme
inducer, and there are numerous drug–drug interactions with carbamazepine.
Oxcarbazepine has substantially fewer drug interactions and does not require
monitoring of CBCs and liver transaminases because it does not form the same
10,11-epoxide metabolite as carbamazepine. It requires monitoring of serum sodium
for the first 3 months of therapy and periodically thereafter, because it may cause
SIADH and hyponatremia. Lamotrigine has few drug interactions except with
valproic acid and does not require any laboratory monitoring. It may, however, cause
a desquamating rash (e.g., Stevens–Johnson syndrome) if the dose is escalated too
quickly. A newer agent, lacosamide, shows modest efficacy for treating DPN but is
not FDA-approved for treating pain.
Topical agents such as local anesthetics and capsaicin are effective for treating
localized areas of neuropathic pain, such as PHN. A 5% lidocaine patch is approved
by the FDA for the treatment of PHN and is particularly helpful for treating allodynia.
It is very well tolerated and easy to apply. It may be cut to the desired shape, and
very minimal local anesthetic penetrates the skin, so there is no systemic toxicity with
proper administration. Various other topical lidocaine products are available (e.g.,
ointments and creams), but most do not penetrate the skin deep enough to reach the
affected nerve endings. Capsaicin depletes substance P in the periphery and
downregulates the transient receptor potential vanilloid 1 (TRPV1) receptors.
Because it is derived from chili peppers, it causes a significant amount of burning
until the substance P is depleted, and many patients do not tolerate the application of
the cream several times daily to accomplish this. Capsaicin cream is available in
several strengths, and there is an FDA-approved 8% patch available for medical
office use which is applied for an hour under local anesthesia and can be reapplied
Opioid analgesics have shown moderate efficacy at best in treating neuropathic
pain and are not usually considered first-line therapy because of potential long-term
effects such as hyperalgesia, tolerance, immunosuppression, and hypogonadism with
20 Tramadol and tapentadol, atypical opioids, have both opioid activity
and SNRI activity and have been shown to be effective in several types of
neuropathic pain. Their adverse effects are similar to those of both opioids and
SNRIs, including constipation, sedation, and possibly seizures, which are a doselimiting effect.
When compared in a systematic review and meta-analysis, all of the first-line
agents and most second-line agents were equally effective with no significant
There are some data that show that a combination of agents, such as an opioid and
a gabapentinoid, or a TCA and a gabapentinoid, may offer more analgesia than either
90,91 This polypharmacy may offer additive analgesia because different
agents act on different parts of the pain-signaling pathways. If more than one agent is
used, lower doses of each may reduce adverse effects. However, polypharmacy adds
complexity to regimens, which may reduce compliance and cause confusion,
particularly in elderly patients.
QUESTION 1: K.J. is a 73-year-old man with a history of Hodgkin lymphoma. He is in remission after
Electrolytes, within normal limits
Which of K.J.’s presenting symptoms are consistent with neuropathic pain and PHN?
K.J. is past the acute phase of his herpes zoster (shingles) pain, but now notices
that the pain has a burning quality, localized over the region where his lesions have
healed. This is quite typical for a PHN presentation. Another feature that indicates a
neuropathic type of pain is his increase in pain with light touch or rubbing of his
clothing (allodynia). It is a localized pain that does not radiate past the dermatomal
distribution of his zoster infection. Opportunistic infections such as herpes zoster are
common in patients who are immunocompromised such as K.J. when he was
CASE 55-4, QUESTION 2: What factors need to be considered when choosing a medication for K.J.?
Which medication is the most appropriate option for treating K.J.’s PHN pain?
POSTHERPETIC NEURALGIA TREATMENT
The American Academy of Neurology (AAN) published PHN treatment guidelines in
2004. Since that time, there have been many more studies published, but there has
been very little change in the approach to treating neuropathic pain. The AAN
guidelines state that TCAs (e.g., amitriptyline, nortriptyline, and desipramine),
gabapentin, pregabalin, opioids, and topical lidocaine patches are effective and
should be used in the treatment of PHN.
105 The International Association for the Study
of Pain has also published guidelines on the general treatment of neuropathic pain.
Ideally, patients should be treated with the most effective therapy that has the
lowest risk of adverse effects. K.J. has peripheral neuropathic pain in a localized
area, which is typical of PHN, so a reasonable first-line choice would be a lidocaine
patch; however, his pain is in a 10- to 12-cm strip that covers a fairly large surface
area from his abdomen to his back. He would need to use at least two patches daily
to cover this area, which is fewer than the maximal recommended dose of three
patches daily, but it would be an effective barrier against the pain of clothing rubbing
against this location. Another localized option would be capsaicin (either as a patch
or a cream). Capsaicin cream is available over the counter and is substantially less
expensive than lidocaine patches. Insurance plans may require a trial of capsaicin
before approving the more expensive lidocaine patch. Unfortunately, many patients
cannot tolerate the burning associated with capsaicin.
Another first-line option would be a TCA, which may help him sleep. However,
he has BPH, and the anticholinergic effects of a TCA may cause increased urinary
retention. These medications also cause orthostatic hypotension and may be a risk for
K.J. if he has to get up during the night to use the bathroom (Table 55-8). An SNRI
A calcium-channel blocking anticonvulsant such as gabapentin is also a
possibility. The sedating effects of gabapentin may help him sleep if his last dose is
given at bedtime, and would not cause the urinary retention, constipation, and
orthostatic hypotension associated with TCA use. Given his age, a slow dose
escalation starting at 100 mg by mouth 3 times a day would be appropriate. The most
important aspect of monitoring for this agent would be for cognitive effects, such as
short-term memory problems or difficulty with word-finding.
If the above options do not provide adequate analgesia, addition of an opioid such
as morphine or oxycodone may be considered due to the potential for additive
analgesia. Initially, a short-acting opioid should be used so that K.J. may be titrated
to the optimal analgesic dose. Tramadol is another alternative with some TCA-like
activity and mild opioid effects. However, if an opioid is added, it may increase the
adverse effects of the above agents, including constipation, sedation, urinary
retention, and cognitive effects. Whenever an opioid is added to a medication
regimen, a bowel regimen must be implemented as well. A commonly used regimen
includes a stool softener such as docusate sodium 100 mg by mouth twice daily or an
osmotic agent such as polyethylene glycol 17 g by mouth daily and a mild stimulant
laxative such as senna 8.6 mg one to two tablets by mouth once daily.
information, what would be an appropriate adjustment in his therapy?
MODIFYING THE NEUROPATHIC PAIN REGIMEN
Adverse cognitive effects like K.J. is having are common with anticonvulsants,
especially in older patients. Problems with memory, concentration, and word-finding
are common. No anticonvulsant is better than any other in this regard; however, some
of the adverse effects are dose-related, and patients may exhibit tolerance to some of
the effects (like sedation) with time. K.J. is at the maximal recommended daily dose
of gabapentin and does not feel that this has been very helpful. At this time, he may
need to be tapered off the gabapentin. Sometimes patients do not notice analgesic
effects of their medications until they are discontinued. It is a good practice to
titrate oral analgesics upward when starting therapy and downward when
discontinuing, to avoid a marked increase in pain and withdrawal syndromes that
have been reported with both antidepressants and some anticonvulsants. He could
reduce his dose by 300 mg every 3 to 5 days until his pain increases or he is off the
A different topical agent would be the lidocaine patch. Because he and his wife
are reporting some signs of depression, an antidepressant may be an option. An
antidepressant was not chosen previously because of concerns about his BPH
symptoms; however, a nontricyclic SNRI agent such as duloxetine may be an
effective alternative to treat his depression as well as his pain, although there are no
studies reporting its effectiveness for this indication. Another option may be to
switch to another anticonvulsant. Pregabalin has very similar pharmacologic activity
to gabapentin, so it may not offer any additional analgesia over gabapentin. Possibly,
a sodium-channel blocking anticonvulsant such as oxcarbazepine could be used for a
trial. However, there are minimal data supporting the sodium-channel blockers for
typical C fiber-mediated pain associated with PHN.
ANALGESIC DRUG–DRUG INTERACTIONS
Antidepressants either increase the concentrations of NE or 5-HT or both. Opioids
also have serotonergic effects, so it is possible to have a net excess of either of these
neurotransmitters, or both. The consequence of an excess of NE is CNS excitation
include muscle rigidity, hyperpyrexia, mental status changes, and possible organ
failure. None of these serious adverse effects are very predictable, although they are
more likely with higher doses of either agent. If opioids are used with
antidepressants, the lowest effective doses should be used, and patients should be
counseled to watch for mental status changes.
Pharmacodynamic interactions are more likely to occur with analgesic
polypharmacy. Because several analgesics may be used together to decrease the
excitatory effects of the pain signal, there is always a risk of additive sedation,
dizziness, or even respiratory depression. Several pharmacokinetic drug–drug
interactions may occur with analgesics as well. In K.J.’s case, his duloxetine and
tramadol are both substrates of cytochrome P-450 2D6 and may compete with each
other for this enzyme. This may alter the blood levels and clinical effects of these
agents. A table of agents commonly used in pain management, the relevant
cytochrome P450 enzyme involved in its metabolism, and potential drug interactions
can be found in Table 55-13. K.J. likely needs an antidepressant for his depression
symptoms, so alternatives will need to be considered.
Drug Interactions with Analgesics
CYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP3A4
Amitriptyline Amitriptyline Amitriptyline Amitriptyline,
Naproxen Celecoxib Citalopram Nortriptyline,
R-warfarin Diclofenac Diazepam Cyclobenzaprine,
Duloxetine Fluoxetine Indomethacin Desipramine,
Methadone Ibuprofen Topiramate Doxepin, paroxetine Codeine, zaleplon
Theophylline Naproxen Fluoxetine, sertraline Cyclobenzaprine,
Tizanidine Piroxicam Hydrocodone,
Phenytoin Fentanyl, duloxetine Lidocaine,
Carbamazepine Carbamazepine Carbamazepine Carbamazepine Carbamazepine
Phenytoin Fluoxetine Phenytoin Phenytoin Oxcarbazepine
Cimetidine Carbamazepine Fluoxetine Celecoxib Fluoxetine
Ciprofloxacin Paroxetine Indomethacin Desipramine Sertraline
Sertraline Paroxetine Fluoxetine Ketoconazole
Valproic acid Topiramate Methadone Cyclosporine
CENTRAL NEUROPATHIC PAIN: POSTSTROKE
Pain is one of the most distressing symptoms after a stroke. As mentioned previously,
poststroke pain is a central pain syndrome, caused by a lesion in the CNS. Sometimes
the cause of central pain syndromes cannot be identified, and even though a stroke
presents with a specific lesion, it is still very difficult to treat. There are several
different types of pain after a stroke and patients may have more than one type.
Nociceptive pain may be related to immobilization, spasticity, and/or muscle
contraction in the event of limb paresis. The shoulder is the most common location
but musculoskeletal/myofascial pain can occur in the upper back and neck, as well as
tension-type headache. The lower extremities may be affected by weakness, muscle
spasms, and/or arthralgias from joint disuse. However, by far the most difficult and
far-reaching pain is central neuropathic pain generated in the CNS, which is called
central poststroke pain (CPSP). CPSP has been reported in as many as 1% to 18% of
106 The diagnostic criteria for CPSP are as follows: (1) pain within
an area of the body corresponding to the lesion of the CNS; (2) history suggestive of
stroke and onset of pain at or after stroke onset; (3) confirmation of a CNS lesion by
imaging or negative or positive sensory signs confined to the area of the body
corresponding to the lesion; and (4) other causes of pain, such as nociceptive or
peripheral neuropathic pain, that are excluded or considered highly unlikely.
clinical presentation of CPSP is similar to other neuropathic pain. The onset of pain
ranges from immediate to several months after stroke. It may affect a small region of
the body or a large area (from head to toe). Central pain after a contralateral stroke is
quite common, particularly after thalamic strokes (e.g., patients with a stroke in the
left side of the brain will have symptoms on the right side of the body). Because the
thalamus is the brain’s “relay station,” any abnormal signaling may be amplified.
Temperature-sensory dysregulation via the spinothalamic tract is common, as well as
dysesthesias and allodynia. It is described as “burning,” “aching,” “squeezing,”
“pricking,” or “cold.” These symptoms are frequently aggravated by a cold
environment, psychological stress, heat, fatigue, or body movement.
There are no guidelines for management of CPSP, and few robust studies exist but
lack data related to comparative efficacy. Therapy is usually done on a trial and error
basis. Current data support use of amitriptyline (with titration from 10 mg/day up to
100 mg/day) as first-line therapy.
109 Nortriptyline may be used as an alternative TCA
in patients who do not tolerate amitriptyline. SNRIs have been shown to be
beneficial for other types of neuropathic pain but not for CPSP. If pain relief is
insufficient, an anticonvulsant may be used. Lamotrigine (titrated to 400 mg/day) may
be added or exchanged for the TCA. It has been shown to have some efficacy for
CPSP and was fairly well tolerated.
110 Other anticonvulsants that have shown
efficacy for both central and peripheral neuropathic pain are listed in Table 55-8.
Opioids have been studied in patients with CPSP but were not effective, and there
112 Other therapies such as intravenous infusions of
lidocaine, morphine, and ketamine are only experimental and are not recommended.
It is not unusual to combine agents with different mechanisms of action, though there
are no data supporting this for CPSP. Monotherapy should be titrated to the maximum
Nociceptive pain such as shoulder pain related to stroke may be treated with
acetaminophen or local/topical agents. NSAIDs are contraindicated due to the
increased risk of myocardial infarction and stroke; however, salicylates may be
considered. Muscle spasms or spasticity is common after a stroke, and this is usually
treated with an antispasticity agent such as baclofen or tizanidine. Skeletal muscle
relaxants are generally not effective for long-term use.
Nonpharmacologic therapies for CPSP include deep brain stimulation, motor
cortex stimulation, and transcranial magnetic stimulation. Physical rehabilitation
(physical and occupational) is essential to help improve function and cognitive
behavioral therapy is used to help patients cope with their new circumstances and
cognitive or physical limitations.
quit because he fellseveral times at work. MRI of the neck showed only a mild disc bulge at C5–C6.
He was holding his head in his hands, wincing periodically. Otherwise his physical examination was
vitalsigns today are as follows:
Respiratory rate, 16 breaths/minute
His pain rating is 9 out of 10.
What symptoms does W.J. have that are consistent with CPSP?
Although W.J. does not have shoulder pain which may be present in CPSP, W.J.
has some localized neck pain. He does not have any obvious injury (e.g., from a fall).
Because he has not been very active, and he sits with his head in his hands or bowed
forward, his neck pain is most likely myofascial. He has frequent headaches that he
localizes to his frontotemporal area.
Because W.J.’s stroke was in his cerebellum, he has notable problems with
balance and vertigo as well as tinnitus. These are not painful but are disturbing and
limit his functionality and predispose him to falling, which may cause injury. He has
intermittent nystagmus which he describes as throbbing. His vision and hearing were
within normal limits so his symptoms are sensory only.
Since his stroke, W.J. has had body tingling affecting all four extremities. He
reports some spontaneous jerking and muscle spasms that affect his extremities
(mostly the right side) and right-sided weakness as well, with some muscle atrophy,
and he reports that this is his most painful and bothersome symptom; however, on
physical examination there is not notable spasticity. He was noted to have decreased
vibratory sensation in his feet and ankles bilaterally. The bilateral presentation is
more consistent with his diabetes. He describes more pain with changes in the
weather and stress, but this is not specific for CPSP.
CASE 55-5, QUESTION 2: Considering W.J.’s comorbidities, what should be recommended for treating his
Treatment goals for W.J. and any stroke patient are to (1) reduce discomfort and
suffering, (2) improve or regain as much function as possible, and (3) improve
coping. Because there is so little known about what causes CPSP, it is difficult to
tailor analgesic therapy. W.J. has diabetes with symptoms suggestive of diabetic
neuropathy. Amitriptyline is considered a first-line therapy for CPSP as well as
diabetic neuropathy. Tricyclic antidepressants are also used for depression (though at
a higher dose) and for headache prophylaxis. It is unknown whether the
anticholinergic effects of the TCA will affect his balance issues, because it may
cause orthostatic hypotension. Of concern is his current use of a rather high dose of
sertraline. SSRIs do not offer any significant analgesia, and the SSRI and TCA
combination will provide additive serotonergic effects, putting W.J. at risk for
serotonin syndrome (Table 55-13). A discussion with his mental healthcare provider
is warranted to review potential analgesic options, including a trial of an SNRI such
as duloxetine. Alternatively, the gabapentinoids may be helpful for his diabetic
neuropathy, though there is less support for CPSP. Lamotrigine is likely a slightly
more effective choice for CPSP, but lacks robust data for use in diabetic neuropathy.
There do not appear to be any drug interactions or contraindications for either type of
W.J. has some musculoskeletal neck pain and may benefit from a trial of
acetaminophen or salicylates or a topical analgesic; however, NSAIDs are
contraindicated due to his history of stroke. He also has some intermittent muscle
spasms that are quite bothersome for him. Typically, the antispasticity agents are
useful so he may benefit from a trial of tizanidine or baclofen (Table 55-11).
Nonpharmacologic therapies such as heat, massage, and physical therapy may be
FUNCTIONAL PAIN SYNDROMES (FPS)
Functional pain syndromes are a cluster of disorders for which the pathophysiologic
mechanisms have not been clearly defined to explain the symptoms.
medically unexplained symptoms for both gastrointestinal and nongastrointestinal
disorders such as dyspepsia, irritable bowel syndrome, fibromyalgia, chronic
fatigue, and interstitial cystitis. There can be overlap in the syndromes with the
presentation of chronic pain and associated psychiatric comorbidities including
depression, anxiety, and posttraumatic stress disorder (PTSD).
Pain that does not conform to anatomic or neurophysiologic findings is often
attributed to psychopathology. Somatic symptom disorder (SSD) is a diagnostic
entity in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders
that replaced somatoform disorder terms including pain disorder, somatization
disorder, and undifferentiated somatoform.
116 Somatic symptoms associated with
significant distress and disruption of daily life are common with FPS. Patients with
FPS often have health concerns manifested by disproportionate and persistent
thoughts of serious symptoms, a high level of anxiety about symptoms, and excessive
time and energy devoted to health concerns.
Fibromyalgia is a chronic debilitating condition with the primary symptoms of
chronic widespread pain and fatigue. It affects between 3 and 6 million people in the
United States, an incidence of 4.9% in women and 2.9% in men.
healthcare costs for patients with fibromyalgia is 3 times those without
It is defined by the American College of Rheumatology (ACR) as
pain that is both chronic (lasting longer than 3 months) and widespread (above and
below the waist and on both sides of the body). The ACR has published new
diagnostic criteria in 2010. They propose using a widespread pain index, in which
patients indicate how many areas of their body have pain, and a symptom severity
scale, in which patients rate the severity of fatigue, waking unrefreshed, and
cognitive and somatic symptoms.
120 Fibromyalgia was previously thought to be
peripherally mediated pain related to an inflammatory or muscular disorder, but it
has been shown that it may be the manifestation of CNS neurotransmitter dysfunction.
Patients with fibromyalgia are more likely to have suffered a traumatic event
previously, such as a motor vehicle accident or childhood sexual abuse.
have shown an imbalance in neurotransmitters in which excitatory neurotransmitters
in the CNS of fibromyalgia patients are increased, including glutamate (a twofold
increase) and substance P (a threefold increase), and inhibitory neurotransmitters,
NE and 5-HT, are decreased. Patients with fibromyalgia have an enhanced
perception of pain at substantially lower forces and at a lower frequency of
stimulation than control patients. Pain sensation has a greater amplitude and is more
Input may be from the periphery or may be triggered by a central
123 Heightened sensitivity to lower stimulus seems to
contribute to the persistent pain with these patients.
124 This can be widespread and
symptoms seem to be largely affected by an exaggerated response to personal
stressors, noxious stimuli (hyperalgesia), and non-noxious sensory stimuli
(allodynia). Fibromyalgia, as a functional pain syndrome, is associated with other
comorbidities that need to be addressed for symptom management, even though
treating these symptoms may not directly benefit the hallmark tenderness associated
with the syndrome. The assessment tool most often used to assess the impact of
fibromyalgia on daily life and function is called the Fibromyalgia Impact
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