QUESTION 1: G.R. is a 38-year-old woman who presents with chronic widespread muscle pain from her
What part of G.R’s presentation supports the presence of a functional pain syndrome?
Williams & Wilkins; 2010:474.)
G.R. likely has fibromyalgia, given her widespread pain that has been present for
more than 3 months and was precipitated by a traumatic event (car accident). She
reports sleeping poorly, fatigue, and the comorbidities of depression and IBS. On
physical examination, she exhibits widespread musculoskeletal tenderness including,
but not limited to, several of the identified fibromyalgia tender points, bilaterally,
both above and below the waist. Her vitamin D level represents a mild deficiency.
CASE 55-6, QUESTION 2: What pharmacologic and nonpharmacologic therapies could be recommended
There have been several evidence-based guidelines published for the treatment of
126–130 These guidelines recommended a multidisciplinary approach with
pharmacologic and nonpharmacologic therapy. Because evidence indicates a CNS
neurotransmitter imbalance, the most effective pharmacologic approaches have
targeted these imbalances. Antidepressants have been shown to reduce pain and
improve function by increasing levels of 5-HT and NE in the CNS. Historically, the
tricyclics (most commonly amitriptyline) have been shown to moderately improve
pain, sleep, and to a smaller extent on fatigue and health-related quality of life
(HRQOL). SSRIs have also shown some improvement in pain, depression, and
HRQOL but the effect sizes were quite small.
131 Duloxetine and milnacipran are both
SNRIs that are FDA-approved for fibromyalgia. Milnacipran appears to have more
NE activity than duloxetine. This difference does not appear to confer a therapeutic
difference. Both of these agents improve average pain scores, FIQ scores, physical
functioning, and overall sense of well-being (Table 55-14).
Gabapentinoids have been shown to reduce the activity of excitatory
neurotransmitters, particularly glutamate. Pregabalin is an anticonvulsant that was
approved by the FDA in 2007 for treating fibromyalgia. It targets the increased levels
of glutamate in the CNS by binding to the α2δ subunit of voltage-gated calcium
channels, preventing release of glutamate from presynaptic terminals (Fig. 55-3).
This agent has been shown to improve average pain scores and patient perception of
improvement, but failed to show improvement in FIQ scores.
134,135 A long-term openlabel study found that patients who did well in the short term maintained an
improvement in pain for up to 6 months compared with placebo.
similar compound, has not been formally approved for fibromyalgia but has support
for its use. Some insurance companies require a trial with gabapentin before
allowing use of pregabalin because of its lower cost.
duloxetine, milnacipran, and pregabalin in fibromyalgia and found that duloxetine and
pregabalin were better than milnacipran in improving pain and sleep.
was better for symptoms of depression, and pregabalin and milnacipran were better
for fatigue. Headache and nausea were more common with duloxetine and
milnacipran, and diarrhea was more common with duloxetine.
Other drug therapies that have shown some benefit in treating fibromyalgia and its
comorbidities include pramipexole, a dopamine agonist, which is beneficial in
treating restless legs symptoms, as well as pain and fatigue.
acetaminophen, and opioids are not recommended for treating fibromyalgia
In fact, Goldenberg, et al. conducted a literature review and found no
evidence from clinical trials that opioids are effective for the treatment of FM. The
studies reviewed found that patients with FM receiving opioids had poorer outcomes
than those receiving nonopioids.
140 More recently, data have been published noting
the effectiveness of low-dose naltrexone, an opioid Mu-receptor agonist, in pain
reduction, as well as improvement in general satisfaction with life and mood.
An appropriate first step for G.R. is to develop a multidisciplinary approach,
including physical rehabilitation, CBT, and pharmacologic therapy adjustments. She
is currently taking an antidepressant (sertraline), which may be helpful for her
depression but is likely not very helpful for her fibromyalgia. It may be possible to
switch her to an SNRI such as duloxetine or milnacipran in consultation with her
mental healthcare provider. She is currently taking tramadol with some relief. She
has not maximized her dose (maximum daily dose is 400 mg); however, she is also
taking an SSRI, which may place her at a higher risk of serotonin syndrome. The risks
and benefits of combining antidepressants with tramadol must be considered on a
patient-by-patient basis. Because she is having trouble sleeping, she could be offered
a trial of amitriptyline or pregabalin, both of which have sedating side effects (Table
55-7). Pregabalin is a recommended agent and has a different mechanism of action
than the medications that she has previously tried. If cost of therapy is a concern, then
gabapentin could be tried instead. A vitamin D supplement should also be considered
to correct her slightly low vitamin D levels. There is not strong evidence supporting
vitamin D supplementation, but there is little harm in correcting her slight deficiency.
Pharmacologic Treatment of Fibromyalgia
Drug Oral Dose Adverse Effects Comments
Amitriptyline 25–50 mg QHS Dry mouth, constipation,
Cyclobenzaprine 10–30 mg QHS Dry mouth, constipation,
Gabapentin 300 mg QHS, titrate to
aFood and Drug Administration–approved to treat fibromyalgia.
BID, 2 times a day; QHS, every night at bedtime; TID, 3 times a day.
Bernardy et al. conducted a systematic review of CBT for fibromyalgia and found
142 Hauser et al. evaluated different regimens of aerobic
activity with a meta-analysis and found that land- and water-based aerobic exercise,
at a slight to moderate intensity, 2 to 3 times a week for at least 4 weeks resulted in
improvement of depressed mood and increased health-related quality of life scores
and physical fitness. This was maintained if the patient continued exercise at home.
Aquatic training is beneficial for improving wellness, symptoms, and fitness in adults
144 Luciano et al found that CBT is more cost-effective that routine
FDA-approved medications for adult FM patients.
Psychological Comorbidity and Opioid Risk
QUESTION 1: M.T. is a 33-year-old woman with chronic abdominal pain. She first experienced recurrent
episodes of abdominal pain at the age of 13 after menarche. At age 21, she was diagnosed with acute
visits, she has been hospitalized 3 times in the past year for abdominal pain.
use of emergency department visits for pain management. M.T. believes her current management with
supply limit increased from 180 to 240 tablets.
ability to work. Her physical examination is unremarkable except for diffuse abdominal tenderness.
What is the clinical relevance of M.T.’s self-description of abdominal pain?
Clinical Relevance of Abdominal Pain
M.T.’s self-report of pain is consistent with functional abdominal pain (FAP). FAP
is more common in women and peaks around the fourth decade of life. Patients with
FAP have high work absenteeism and healthcare utilization.
diagnosis of FAP include abdominal pain that is present for at least 6 months and is
not related to gastrointestinal function. The patient will often have a decrease in daily
activity with time. The principal criterion differentiating FAP from other
gastrointestinal disorders, such as pancreatitis, is constant pain that lacks symptom
relationship to food intake or defecation. Psychological disturbances are more likely
when pain has persisted for a long period and manifests as symptom-related
behaviors that dominate a patient’s life (Table 55-15).
Symptom-Related Behaviors of Functional Abdominal Pain
Expressing pain of varying intensity through verbal and nonverbal methods
Urgent reporting of intense symptoms disproportionate to available clinical and laboratory data
depression to presence of pain
Requesting diagnostic studies or surgery to validate the condition as “organic”
Focusing attention on complete relief of symptoms
Taking limited personal responsibility for self-management
Making requests for narcotic analgesics when other treatment options have been implemented
From the physiologic perspective, M.T.’s abdominal pain most likely originated
from a combination of somatic and visceral components associated with menses and
pancreatitis. When the pain symptoms occur frequently in conjunction with a stressor
as in FAP, the main mechanism for altered pain regulation relates to the failure to
inhibit the amplification of normal regulatory afferent input from the gut to central
mechanisms in the prefrontal, cingulated cortex, and limbic structures (e.g., cognitive
and emotions centers of the brain). This impairment in homeostatic inhibition of pain
may be related to low levels of 5-HT, NE, endorphin, and other neuropeptides that
mediate descending pain transmission in the CNS. Recognition of the brain–gut axis
in FAP is essential to understanding its clinical presentation, diagnosis, and
FUNCTIONAL ABDOMINAL PAIN TREATMENT
CASE 55-7, QUESTION 2: What are the current recommendations for pharmacologic treatment of FAP?
What approaches to the management of FAP are appropriate for M.T.?
Pharmacotherapy for patients with FAP is empirical and not based on results from
well-designed clinical trials. Clinical trials have not been targeted to this diagnostic
entity, so treatments are typically designed on the basis of data from other chronic
pain disorders. The cornerstone to management depends on an effective relationship
between the clinician and patient. In this case, the primary care physician needs to
listen to M.T.’s concerns but set realistic and consistent limits when ordering tests,
medical interventions, and medications. M.T. needs to be an active participant in the
pain management plan and take responsibility for self-care.
Antidepressants, such as TCAs in low daily dosages, may be useful in treating
FAP for both pain and depression owing to their combined noradrenergic and
In other chronic pain conditions, TCAs generally have been
more successful than using SSRIs.
128 Medications with combined 5-HT and NE
reuptake activity (e.g., SNRIs such as venlafaxine and duloxetine) have recognized
pain-reducing effects with somatic pain conditions and may be useful in FAP. To
ensure treatment adherence, M.T. needs affirmation that antidepressant is not
prescribed simply to treat depression. It is important that the clinician educate the
patient on the role of antidepressants in the treatment of pain. Patient education
resources such as diagrams help to show the physiologic basis for treatment of pain
and describe descending inhibitory pathways.
Gabapentin and pregabalin clinical trials have established their efficacy for
neuropathic pain and fibromyalgia, but benefit for visceral or central pain syndromes
is not established. NSAIDs offer little benefit because their action is located in the
peripheral nervous system. Long-term treatment with benzodiazepines is not
recommended because of the abuse potential and tendency to interact with other
medications. For patients who are refractory to usual doses of antidepressant
medication, referral to psychiatry should be made for treatment with atypical
antipsychotic agents such as quetiapine.
CASE 55-7, QUESTION 3: There is concern about M.T.’s use of alcohol and escalating use of opioid
medication. What is the risk that M.T. will become addicted to opioids?
Opioid use behaviors are stratified based on the risk of aberrant drug use.
Aberrant drug use behaviors may occur along a spectrum from those less suggestive
of addiction, such as an occasional, sanctioned increase in the opioid dose by a
medical provider, to those that may be more suggestive of addiction, such as injecting
oral formulations. Table 55-16 provides a list of risk factors for opioid misuse.
Important but less consistent risk factors include pain-related functional impairment
such as sleep disturbance, mental health issues, history of child sexual abuse or
151,152 With respect to gender, women with chronic pain
who report significant emotional issues were at increased risk for opioid misuse.
M.T. has multiple behaviors in which some are more indicative of addiction such
as concomitant alcohol use whereas others can be explained given the etiology of
FAP. For example, high healthcare utilization for pain validation is common in
patients with FAP. Also, aggressive complaining about the need for more opioid
medication may be driven by M.T.’s perception that the current dose prescribed by
her primary care physician no longer relieves her pain, implying tolerance has
The factor that is most concerning for addiction is M.T.’s continued use of alcohol
despite previous pancreatitis and misusing it to treat anxiety. There is also a risk of
increased opioid side effects, especially sedation and respiratory depression, with
concurrent use of alcohol. Multiple literature reports have confirmed there is a strong
association between alcohol abuse and opioid addiction.
155,156 Guidelines for chronic
opioid therapy strongly recommend clinicians conduct a risk assessment of substance
abuse, misuse, or addiction before initiating opioid therapy.
Risk Factors for Opioid Addiction
Concurrent abuse of alcohol or illicit drugs
Multiple dose escalations or other nonadherence with therapy despite warnings
Obtaining prescription drugs from nonmedicalsources
Repeatedly seeking prescriptions from other physicians or emergency departments
Stealing or borrowing drugs from others
Misuse Taking a prescription for a reason or at a dose or frequency other than for which it was
Use of a medication for a nonmedical use, or for reasons other than prescribed. For
example, altering dosing or sharing medicines, which has harmful or potentially harmful
Abuse Misuse with consequences involving the use of a substance to modify or control mood or
state of mind in a manner that is illegal or harmful to oneself or others. Potentially harmful
consequences include accidents, injuries, blackouts, legal problems, and sexual behavior
that increases the risk of infectious diseases.
Addiction A primary, chronic, neurobiologic disease with genetic, psychosocial, and environmental
factors influencing its development and manifestations. It is characterized by behaviors
that include one or more of the following: impaired control over drug use, compulsive use,
continued use despite harm, and craving.
be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug,
or administration of an antagonist.
by a desire for pain relief (e.g., constantly watching the clock to dose medication “on
time” so pain does not become severe).
Tolerance A state of adaptation in which exposure to a drug induces changes that result in a
diminution of one or more opioid effects with time.
Assessment of Chronic Opioid Therapy
CASE 55-7, QUESTION 4: M.T. would like to continue with opioid therapy despite the concerns of her
primary care physician. Is M.T. a candidate for chronic opioid therapy?
The Centers for Disease Control released new recommendations for opioid
therapy that support the establishment of a treatment plan with the patient before
starting opioid therapy that includes realistic goals for pain and function along with
consideration of when therapy will be discontinued if benefits do not outweigh risks.
Clinicians should continue opioid therapy only if there is clinically meaningful
improvement in pain and function that outweighs risks to patient safety.
of MT, a pain agreement (e.g., contract) should be established even if the goal is to
eventually discontinue opioid therapy. There are multiple sources in the literature for
information and guidelines on written agreements between the clinician and patient
for chronic opioid therapy (COT).
The written COT agreement should include goals of therapy, how opioids will be
prescribed and taken, expectations for follow-up and monitoring, alternatives to
COT, expectations regarding use of concomitant therapies, and potential for tapering
the regimen and discontinuing.
Indications for tapering and/or discontinuation of
the opioid include failure to make progress toward therapeutic goals, intolerable
adverse effects, or repeated or serious aberrant drug-related behaviors. Patient
compliance requirements within the written agreement should include random urine
drug screens for illicit substances or opioids obtained from other sources and limited
prescribing (e.g., reduced quantities, biweekly prescribing) to help the patient
manage use if necessary. In this case, M.T. has not made progress in meeting the goal
of decreased emergency department utilization, she continues to use alcohol with her
medication, and she has been resistant to trying other therapies despite the
ineffectiveness of opioids in treating her pain. These behaviors would indicate M.T.
Screening tools that assess the potential risks for opioid misuse based on patient
characteristics are helpful in determining eligibility for COT. Patient self-report
questionnaires for assessing risk of aberrant drug-related behavior include the
Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R) and the
The Diagnosis, Intractability, Risk, Efficacy (DIRE) tool is a clinician evaluation
instrument designed to assess the potential efficacy of chronic opioid therapy as well
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