Miscellaneous Pain Syndromes in Older Adults
Persistent pain is a common problem in older adults, affecting 25-50% of community-dwelling elderly persons and 45-80% of older residents of long-term care facilities.1 Several painful conditions occur more commonly in older than in younger adults and often go unrecognized. These include polymyalgia rheumatica, giant cell arteritis, fibromyalgia, myofascial pain syndrome, peripheral vascular disease, and leg cramps. These conditions may coexist with other painful disorders, and when untreated, may lead to a decline of functional status and quality of life, depression, falls, and increased healthcare utilization.1 The purpose of this article is to review the assessment, clinical manifestations, and treatment of these disorders.
The treatment recommendations in this article reflect the principles of “Pharmacological Management of Persistent Pain in Older Persons,” published by the American Geriatrics Society (AGS) in 2009.1 Among the most important of these is a thoughtful individualized risk-benefit assessment prior to the initiation of therapy, balancing quality of life with safety.1 Dosing recommendations for many analgesics may be difficult to obtain, as they have not been systematically studied in older adults.1 Additionally, analgesics affect numerous receptor systems, some of which may be compromised by diseases and/or by age-related changes, making side effects less predictable.1 Therefore, as is common in geriatrics, the adage of “start low and go slow” is crucial when using medications for treating pain symptoms.1
The AGS guidelines also recommend the least invasive route of drug administration when possible, the use of around-the-clock dosing for continuous pain, and the use of short-acting medications for breakthrough pain on an as-needed (prn) basis. However, patients with cognitive impairment may not be able to request prn medications.1 This situation may necessitate the use of less well-studied routes of administration and the assistance of caregivers to provide optimal management.1 In many cases, the use of several medications with differing mechanisms of action may provide greater benefit while minimizing side effects when compared to escalating the dose of a single agent.1 An understanding of the side-effect and drug-interaction profiles of the medication combination will minimize additive side effects or deleterious drug-drug interactions.
Polymyalgia rheumatica (PMR) is almost exclusively a disease of older adults, affecting approximately 1% of patients over the age of 50.2 The etiology of PMR is not completely understood. It is postulated that environmental and genetic factors are involved in the pathogenesis of PMR.3 The most common manifestations of PMR include persistent aching pain, discomfort, and morning stiffness in the shoulders, hip girdles, neck, and torso. Pain and discomfort of PMR are most likely related to synovitis and bursitis of the affected joints. The symptoms of PMR tend to be symmetric and interfere with the patient’s capacity to perform activities that involve upper and lower extremities, such as combing hair, fastening a bra, putting on a shirt or a jacket, pulling on socks, walking, and rising from a chair. Other symptoms of PMR may include malaise, fatigue, poor appetite, weight loss, fever, and depression. Swelling and pitting edema of the hands, wrists, ankles, and dorsa of the feet may also occur.
Physical examination reveals decreased range of motion of shoulders, hips, and neck. Muscle tenderness and/or weakness are not prominent features, but joint tenderness may be elicited on examination when synovitis and bursitis are present. Muscle atrophy and weakness may develop from disuse secondary to persistent pain and discomfort.
The characteristic laboratory finding in PMR is a high erythrocyte sedimentation rate (ESR) that can exceed 100 mm/h.4 However, values below 40 mm/h may also be seen in patients with limited disease, less systemic symptoms, and in those previously treated with glucocorticoids.5 Elevated levels of C-reactive protein (CRP) are also found in PMR. Limited evidence suggests that elevated serum CRP is more sensitive than a high ESR for the diagnosis and detection of relapses.6 Normocytic anemia may be present in patients with PMR. Serologic tests for rheumatologic disorders, such as rheumatoid factor and antinuclear antibodies, are typically negative in PMR.
Radiographs of affected joints rarely reveal abnormalities in patients with PMR. Magnetic resonance imaging may confirm inflammation of extra-articular synovial structures. Bursa ultrasonography often reveals effusions within shoulder bursae.
There are no universally-established criteria for the diagnosis of PMR. Some authors recommend the following criteria4:
- Bilateral aching and morning stiffness (lasting ≥ 30 min) persisting for at least 1 month, and involving at least two of the following three areas: neck or torso; shoulders and proximal regions of the arms; and hips or proximal aspects of the thighs
- Age 50 years or older at onset
- ESR (Westergren) increased to 40 mm/h or more
- Exclusion of other diseases
The diagnosis of PMR can be difficult in patients with atypical presentations including age younger than 50 years, asymmetric symptoms, and an ESR below 40 mm/h.
A recent systematic review of the literature in PMR identified the lack of consistency in criteria for diagnosis, treatment regimens, and outcome measures; however, it confirmed that corticosteroids are the recommended therapy for PMR and that prednisone is the corticosteroid of choice.7 If PMR is not accompanied by giant cell arteritis, prednisone 10-20 mg per day generally provides improvement in musculoskeletal aching and stiffness within days.3 The goal of therapy is to reduce symptoms using a minimal dose of corticosteroids. Some recommend a maximum prednisone dose of 20 mg per day,8 and others indicate that patients may occasionally require 30 mg per day; the diagnosis should be questioned if symptoms are unresponsive within 1 week.3 The initial dose should be continued for 2-3 weeks, and then may be decreased by 2.5 mg every 2 weeks down to 10 mg per day; further dose reductions should be by 1-2.5 mg every 1-2 months until off.3,7/ Relapse may correlate with high initial prednisone dose and rapid prednisone dose taper.3,7 Patients often require treatment for 2-3 years; relapse rates vary and have been reported to occur in 33% of patients within the first year7 while others report that up to 10% of patients relapse within 10 years.8 If relapse occurs while off corticosteroids, one may restart the same dose of prednisone that was originally effective.8 The recommended dose of prednisone is the dose that keeps symptoms in remission; some chronic cases may respond to as little as 2.5-5 mg per day.8 One may use ESR and CRP to monitor disease and prednisone dose,3 but the dose of prednisone should not be raised in response to elevated inflammatory markers.8 Persistent elevation of the markers may indicate other underlying conditions.8
Other medication choices may include methotrexate (MTX) if started at onset and continued for at least 1 year (at least 10 mg/wk) or tumor necrosis factor (TNF)-alpha blockers in steroid refractory patients,3,7 but neither is well studied and neither is recommended.8 In PMR, infliximab appears to be ineffective,3,7 as are nonsteroidal anti-inflammatory drugs (NSAIDs).8
Medication side effects, potential drug interactions, and pharmacokinetics. Corticosteroids are associated with many potential side effects that are often related to the patient’s age and cumulative steroid dose.3 Major side effects include osteoporosis, bone fractures, avascular necrosis, new-onset diabetes mellitus, hyperlipidemia, gastrointestinal (GI) bleeding, hypertension, and infections.3 Central nervous system changes are especially concerning in older adults and include insomnia, confusion, psychosis, depression, anxiety, and agitation.9 Electrolyte changes include hypokalemia and hypernatremia; cardiac conduction changes, fluid retention, and heart failure exacerbation are also potential concerns.9 Prolonged use is associated with cataract formation, thinning of the skin, ease of bruising, pituitary axis suppression, nausea, weight gain, decreased muscle mass, and muscle weakness.9
Oral corticosteroids are best taken with food or milk to decrease the potential for dyspepsia. When used for periods longer than about 2 weeks, one should strongly consider dietary or supplemental calcium, vitamin D, vitamin C, and folic acid.9 If there are no contraindications to use, consider the addition of a bisphosphonate for patients with an abnormal bone mineral density scan (T-score < -1 standard deviation).3 Routine monitoring should consist of electrolytes, bone density, blood pressure, blood glucose, and eye exams.
Prednisone is a prodrug that must be metabolized in the liver to its active form, prednisolone; this conversion may be impaired in patients with significant liver disease. Prednisolone is commercially available in an oral product if needed, and the two drugs are equivalent on a mg-per-mg basis.9 Prednisone is metabolized in many tissues and also in the liver, weakly by the cytochrome P450 (CYP450) 3A4 isoenzyme; it also is a weak inducer of CYP2C19 and 3A4. Inhibitors of CYP3A4 (eg, aprepitant, cimetidine, clarithromycin, diltiazem, erythromycin, fluconazole, grapefruit, itraconazole, ketoconazole, nefazodone, verapamil) may increase the prednisone blood concentration, whereas inducers of this enzyme (eg, barbiturates, carbamazepine, rifabutin, rifampin) may decrease the prednisone blood concentration. In turn, via enzyme induction, prednisone may decrease the blood concentration of several drugs including, but not limited to, amiodarone, aripiprazole, atorvastatin, carbamazepine, clopidogrel, dronedarone, erythromycin, felodipine, lovastatin, methadone, simvastatin, verapamil, and warfarin. Due to complex interactions, however, prednisone may either increase or decrease the INR in patients taking warfarin. One should use caution when combining prednisone with other medications that may cause hypokalemia, such as diuretics.9 The concurrent use of prednisone with NSAIDs, salicylates, antiplatelet drugs, and/or warfarin increases the risk of GI bleeding and other, less severe GI adverse effects.9 The concurrent use of prednisone and fluoroquinolones may result in the rare potential for an increased risk of tendon rupture, especially in older adults.9 Live vaccines should be avoided in patients taking corticosteroids due the immunosuppressive effects of the steroids; one should wait at least 1 month after the last dose of corticosteroid to administer the vaccine.9 One should separate the dose of bile acid sequestrants or antacids with corticosteroids by approximately 2 hours to avoid decreasing the systemic absorption of the steroid.9
Giant Cell Arteritis (Temporal Arteritis)
Giant cell arteritis (GCA) is a vasculitis of medium and large vessels that occurs predominantly in patients over the age of 50. The disease is generalized, and most of the symptoms result from the vascular inflammation involving the cranial branches of the arteries that originate from the aortic arch. Involvement of the thoracic and abdominal aorta and peripheral arteries may also occur.
While the exact etiology of GCA is unknown, environmental and genetic factors, as well as infectious agents, are suggested as potential triggers for the disease.3,10 Clinical symptoms of GCA include systemic symptoms such as malaise, fatigue, anorexia, weight loss, and fevers. Symptoms related to inflammation of cranial arteries include visual disturbance (eg, diplopia, amaurosis fugax, visual loss), temporal headaches, scalp tenderness, jaw claudication, dysphagia, and tongue claudication. Patients may present with claudication of upper and lower extremities, myocardial infarction, and chest pain.4 PMR symptoms occur in approximately 50% of patients with GCA, and in those cases, patients may present with aching and morning stiffness in the shoulders, hips, neck, and torso, in addition to the symptoms associated with GCA.4
GCA can frequently be diagnosed based on the clinical symptoms; however, temporal artery biopsy remains the gold standard procedure.4 One should obtain a biopsy specimen of the artery of at least 2-4 centimeters in length because the vascular inflammation tends to occur in skip lesions along the length of the artery.4 The American College of Rheumatology (ACR) established criteria for the classification of GCA, which includes three or more of the following11:
- Age 50 years or older
- New onset of localized headache
- Temporal artery tenderness or decreased temporal artery pulse
- ESR 50 mm/h or greater
- Abnormal temporal artery biopsy
Doppler ultrasonography of the temporal arteries has been studied as a diagnostic tool in GCA, and decreased blood flow and velocity in the superficial temporal artery have been identified in GCA when Doppler ultrasonography is used as a diagnostic tool for GCA.12
The treatment of choice for GCA is oral corticosteroids started as soon as the diagnosis is confirmed or strongly suspected.3 As in PMR, prednisone is typically the corticosteroid of choice. It should be initiated at 40-60 mg per day, either as a single dose or in divided doses.3 Alternate-day dosing appears to be associated with a higher rate of treatment failure than daily dosing (70% vs 20%), and therefore is not recommended.3 The dose should be increased if prompt symptom response does not occur.3 The initial dose should be continued for 2-4 weeks until all symptoms have resolved and the acute-phase reactants (ESR and/or CRP) on laboratory testing have returned to baseline.3 Some, however, suggest that ESR is not sensitive for detecting disease reactivation during corticosteroid withdrawal; interleukin-6 levels are more sensitive but are not usually readily available.13 After about 2 months of therapy from the time of symptom response, one may initiate a slow taper, with a maximal dose reduction of approximately 10% of the total daily dose every 2 weeks until 10 mg per day is reached; further dose reductions should be done on a monthly basis, by 1-2.5 mg per day until off.14 Most patients, however, continue treatment for up to 1-2 years.3 Disease flares are common if the corticosteroids are tapered too quickly. Flares may recur during the taper phase and are reported in over 50% of patients, typically within the first 12-16 months when the dose of prednisone has reached approximately 5-10 mg per day.3 Some patients require oral corticosteroids for several years if they have chronic relapsing disease.3
Vision loss is often irreversible if it occurs prior to treatment.3 If vision loss is recent, some recommend intravenous methylprednisolone (1 g daily for 3 days), but there is no solid evidence that this is superior to oral prednisone.3
As with corticosteroid treatment for PMR, one should review the potential drug interactions and monitor and potentially treat for anticipated side effects such as osteoporosis, GI bleeding, hypokalemia, and hyperglycemia.
Aspirin may decrease the ischemic complications of GCA, and although large prospective studies have not yet been done, some advocate the concurrent use of low-dose aspirin with oral corticosteroids (and a proton pump inhibitor for upper GI prophylaxis) if there are no contraindications.3
MTX has been studied for recent-onset GCA, but the results are inconclusive.3 There is some suggestion that MTX may be an option for patients in whom corticosteroids may pose substantial risk (eg, persons with diabetes, severe osteoporosis, severe hypertension).3 Studies used doses of 7.5-15 mg per week. Other agents such as azathioprine and TNF-alpha blockers do not appear to be effective, but infliximab may be an option for patients who do not respond to corticosteroids.3
Fibromyalgia (FM) is a common cause of generalized musculoskeletal pain in older adults. The prevalence of this disorder increases with age and is ten times more common in females.15 The pathogenesis of FM is not well understood. It appears to involve abnormalities in pain processing in the central nervous system and a heightened response to stress. Other triggers have been associated with trauma, infections, and chronic emotional stress.
Patients typically present with diffuse chronic musculoskeletal pain involving the neck, back, chest wall, arms, and legs. Pain is often aggravated by physical exertion, stress, lack of sleep, and weather changes. Other symptoms include numbness, tingling, crawling sensation, and a sensation of swelling without objective evidence of swelling on physical examination.16 Patients may have poorly defined pain symptoms including chest wall pain, abdominal pain, irritable bowel syndrome, bladder symptoms, and pelvic pain. Headache and fatigue are very common symptoms in patients with FM. Additional symptoms may include dry eyes, allergic symptoms, dyspnea, dysphagia, sexual dysfunction, vulvodynia, night sweats, weight fluctuations, and orthostatic intolerance.
The diagnosis of FM is based largely on the patient’s clinical symptoms of chronic, generalized musculoskeletal pain and associated symptoms including fatigue, headaches, sleep disturbances, cognitive difficulties, and mood disturbances. The physical examination of patients with FM is usually unremarkable except for multiple tender points. The ACR proposed criteria for diagnosis includes at least three months of diffuse widespread pain involving bilateral upper and lower body with axial involvement and at least 11 of 18 tender points on examination.17 Initial laboratory testing for FM should include a complete blood cell count, ESR, chemistry panel, thyroid function test, muscle enzymes, and liver enzymes to rule out other pathology.
The management of FM requires a multidisciplinary team to address the physical and psychiatric aspects of the disease. Patients should be educated about the disease process and about the strategies that are available to improve symptom control and to restore quality of life. Engaging in a graded exercise program such as walking, stationary cycling, water therapy, and swimming is essential for a good outcome.18
The American Pain Society (APS) published a set of consensus guidelines for the management of FM in 2005, though portions of these guidelines maynot be appropriate in all older adults.19 Also of note is that these guidelines were published prior to the Food and Drug Administration (FDA) approval of pregabalin (June 2007), duloxetine (June 2008), and milnacipran (January 2009) for the treatment of FM. Excerpts from the APS recommendations are as follows19:
- For initial treatment, use a tricyclic antidepressant (TCA) for sleep.
- Use selective serotonin reuptake inhibitors (SSRIs) alone or in combination with TCAs for pain relief. The doses of all antidepressants should be individualized and concurrent mood disorders treated.
- Do not use a NSAID for primary pain relief. There is no evidence that NSAIDs alone are effective for pain associated with FM.
- Use tramadol for pain relief, alone or in combination with acetaminophen. The dose of tramadol should be titrated slowly when started and tapered slowly when discontinued.
- Use opioids only when all other therapies (pharmacologic and nonpharmacologic) have been trialed.
- Use sedative-hypnotics and anxiolytics such as trazodone, benzodiazepines, nonbenzodiazepine sedatives, or L-dopa with carbidopa especially if sleep disturbances and/or restless legs are present.
- Do not use corticosteroids for the treatment of FM unless there is concurrent joint, bursa, or tendon inflammation.
The European League Against Rheumatism (EULAR) published very similar guidelines differing in its additional recommendation of trials of pregabalin, pramipexole, and milnacipran for FM pain.20 Of note, the EULAR guidelines recommend against the use of strong opioids for FM pain.20
Clinicians are reminded that the prescribing information for all FDA-approved antidepressants and antiseizure medications contain warnings regarding the association of an increased risk of suicide with the use of these drugs. One must use appropriate caution and monitoring when initiating and titrating these medications.
Antidepressants: TCAs. Although none of the TCAs are FDA-approved for analgesia, amitriptyline is the most widely studied TCA for managing FM symptoms and appears to be effective in about one-third of patients, typically within the first 2 weeks of use.18 Nortriptyline is the active metabolite of amitriptyline and is also likely beneficial. However, in older adults, TCAs are not considered appropriate for use due to their strong anticholinergic properties and effects on cognition; the AGS guidelines strongly recommend that the tertiary TCAs (amitriptyline, doxepin, clomipramine, imipramine) be avoided in older adults.1 If determined appropriate for use in individual cases, the lowest effective dose should be maintained. The initial dose for either amitriptyline or nortriptyline is 10 mg daily and may be slowly titrated up to 50 mg daily, typically at bedtime. It is important to note that the analgesic dose of TCAs is usually much less than that utilized for depression.21,22 One may use TCA blood concentrations to monitor for toxicity; there is no benefit to assess analgesia.22
TCAs and serotonin-norepinephrine reuptake inhibitors (SNRIs) all appear to provide analgesia by blocking the reuptake of norepinephrine and serotonin (5HT), which in turn enhances the transmission of these neurotransmitters in the descending inhibitory pathways of the brain and spinal cord.23 TCAs also appear to block sodium channels,21,24 and with chronic use may also decrease gamma-aminobutyric acid type b (GABA-b) and N-methyl-D-aspartate glutamate receptors.25
As previously stated, TCAs are associated with side effects that are often problematic in the older adult. Although all TCAs have anticholinergic properties, the tertiary amines are stronger anticholinergics than the secondary amines (desipramine, nortriptyline). From a side effect standpoint, the secondary amines are considered first line, but they still possess potential risks in the older adult. Anticholinergic effects include sedation, urinary retention, constipation, blurred vision, cognitive changes, and dry mouth; they may also cause acute angle-closure glaucoma. Tachycardia may occur as a result of excessive cholinergic-blocking effects. In addition, TCAs are alpha-1 antagonists (causing orthostasis, vasomotor rhinitis, sedation) and antihistamines (causing sedation, weight gain). They are also associated with cardiotoxicity (QT prolongation, heart block, arrhythmias).21 There may be an increased risk of sudden cardiac death at TCA dosages of 100 mg per day or higher.26 Due to many of the aforementioned side effects, TCAs can contribute to the risk of falls and can be fatal in intentional—or unintentional—overdoses. Of note, the muscle relaxant cyclobenzaprine18 and the antiseizure drug carbamazepine are each structurally similar to TCAs and share many (but not all) of the same side effects.
TCAs are hepatically metabolized and implicated in drug interactions involving primarily the CYP2D6 isoenzyme system. For example, many SSRIs inhibit CYP2D6, which in turn inhibits the metabolism of many of the TCAs, causing sometimes clinically significant increases in TCA blood levels. Of the SSRIs, citalopram and escitalopram seem to have the lowest propensity to cause this interaction. In addition, TCAs, SSRIs, SNRIs, and many other medications increase serotonin levels; concurrent use of multiple serotonergic medications has additive serotonin effects and may result in serotonin syndrome.
Patients may experience a TCA withdrawal syndrome when TCAs are stopped abruptly or insufficiently tapered. Withdrawal symptoms may include restlessness, insomnia, muscle aches, headache, nausea, diarrhea, drowsiness, nightmares, irritability, and movement disorders.22 The duration of the TCA taper depends upon the dose and duration of use, but in general, it should be tapered slowly over 2-4 weeks22; however, if the dose is high or the duration is in years rather than months, consider a slower titration, perhaps over several months.
Antidepressants: SSRIs. The SSRIs include medications such as fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, and escitalopram, and were thought to be relatively ineffective for the treatment of FM symptoms. 18,23 However, some studies indicate that higher-dose fluoxetine (up to 80 mg/day) may improve pain in patients with FM.18 Older adults, however, may not tolerate the higher doses of SSRIs. It also appears from one small trial of middle-aged adults that the combination of fluoxetine with amitriptyline was better than either drug alone.18 It is possible, though, that the CYP2D6 inhibition of amitriptyline by fluoxetine increased the blood levels of amitriptyline and contributed to the beneficial effect.
Antidepressants: SNRIs. The SNRIs include duloxetine, venlafaxine, desvenlafaxine, and milnacipran. Both duloxetine and milnacipran are FDA-approved for the treatment of FM (at doses of 60 mg/day and 100 mg/day, respectively, in younger adults). Venlafaxine and desvenlafaxine (the marketed active metabolite of venlafaxine) are not FDA-approved for FM. The mechanism of action of all SNRIs is similar to the TCAs regarding the reuptake inhibition of norepinephrine and 5HT. Duloxetine inhibits the reuptake of both of these neurotransmitters at FDA-approved doses; venlafaxine inhibits 5HT reuptake at lower doses, but its effects on norepinephrine reuptake typically occur at higher doses.23
The SNRIs are usually better tolerated than TCAs and are associated with fewer toxicities. Duloxetine has minimal effects on adrenergic, cholinergic, dopaminergic, histamine, opioid, GABA, or glutamate receptors,27 and venlafaxine has minimal effects on the alpha-1, muscarinic, or H1 histamine receptors.28 Both duloxetine and venlafaxine may cause dose-related increases in blood pressure.1 Duloxetine is associated with hepatotoxicity and should be avoided in patients with clinically significant liver disease or those with substantial alcohol intake.27 It is also associated with urinary retention and should be avoided or used with caution in patients with pre-existing symptoms.27 Duloxetine is associated with multiple drug interactions, primarily CYP450-mediated.1 Both duloxetine and venlafaxine should be dose-adjusted in renal insufficiency. Of note, venlafaxine is available in an immediate-release formulation (dosed 2 or 3 times/day) and an extended-release formulation (dosed 1 or 2 times/day).
Milnacipran is also an SNRI but with a slight selectivity for norepinephrine over serotonin reuptake inhibition.18 The recommended dose is 100 mg per day, but doses up to 200 mg per day have been used; it should be given in 2 divided doses and titrated slowly over at least 1 week.29 The dose should be reduced in patients with moderate-to-severe renal function. The higher drug concentration seen in older adults is likely related to renal function; the dose should be reduced accordingly. Milnacipran accumulates in patients with severe hepatic impairment.29 Liver toxicity has occurred and ranges from mild transaminase elevation to rare cases of fulminant hepatitis. Do not use concomitantly with alcohol or in chronic liver disease; monitor liver function periodically.29 Seizures have been reported with the use of milnacipran. Avoid use in patients taking monoamine oxidase inhibitors and in those with uncontrolled narrow-angle glaucoma.29 As with other SNRIs, monitor for suicidality, serotonin syndrome, increased blood pressure and heart rate, hyponatremia, dysuria, and abnormal bleeding (likely due to serotonin reuptake inhibition in the platelets). The most common side effects are nausea, constipation, hot flashes, hyperhidrosis, vomiting, palpitations, increased heart rate, dry mouth, and hypertension.29 As with most other medications, milnacipran should be tapered rather than stopped abruptly to avoid a withdrawal syndrome.
Muscle relaxants. Muscle relaxants such as cyclobenzaprine may be used to assist with FM pain and sleep disturbances, at doses of 10-40 mg per day (in younger adults), and is considered to be a TCA devoid of antidepressant properties.18 Long-term use appears to be no better than placebo18; studies supporting its use in FM were short term and used small sample sizes.23 The AGS guidelines describe cyclobenzaprine as “essentially identical to amitriptyline,”1 and, therefore, carries the same potential for toxicity. It should not be used in combination with other TCAs.
Alpha-2 delta ligands (pregabalin and gabapentin). Both pregabalin and gabapentin bind to the alpha-2 delta subunit of the calcium channel to decrease the release of glutamate (excitatory neurotransmitter) and substance P into the neuronal synapse.26,30 Pregabalin is FDA-approved for the management of FM (at 350-400 mg/day in younger adults), and gabapentin is not.
Pregabalin decreases pain and fatigue, and improves sleep and health-related quality of life in patients with FM.18 A short-term trial (8 wk) using a dose of 450 mg per day was more effective than placebo in pain reduction.18 Gabapentin also appears to be effective for pain, sleep quality, and quality of life in FM; the average dose was 1800 mg per day and ranged from 1200-2400 mg per day.18 Because both of these medications are renally eliminated, the minimally-effective dose in an older adult is typically less than that of a younger adult.
Pregabalin and gabapentin share a similar side-effect profile. A slow dose titration often minimizes the occurrence and severity of side effects. In most studies and in clinical practice, drowsiness is the most common side effect.30 This may be beneficial in patients who have difficulty sleeping, but may have adverse consequences if it occurs at unwanted times. Dizziness is also a common side effect,30 and cognitive changes and gait impairment may also occur.26 Consider each patient carefully when contemplating use. In addition, both gabapentin and pregabalin are associated with peripheral edema and weight gain,30 sometimes, but not always, dose-related. Pregabalin may cause dry mouth and blurred vision, and in premarketing trials, though not common, was associated with creatine kinase elevations, decreased platelet count, and a prolonged P-R interval change on electrocardiogram.31
Neither medication is hepatically metabolized and they are therefore safe to use in hepatic impairment. Each must be dose-adjusted for renal insufficiency, however, and each has specific dosing guidelines contained in the manufacturer’s prescribing information.31,32 Anecdotally, older adults typically respond to lower doses and require a longer titration than younger adults. Both medications should be tapered off over at least 1 week, longer depending on the dose and duration of therapy; abrupt withdrawal is reported to precipitate seizures in some individuals.31
It is interesting to note that gabapentin, but not pregabalin, relies on a carrier molecule in the intestinal tract for systemic absorption, and perhaps at various other tissue sites.33 This carrier molecule can become saturated at high doses of gabapentin, causing the excess gabapentin to be eliminated prior to absorption. If given in 3 doses per day, only 60% of 900 mg per day, 47% of 1200 mg per day, 34% of 2400 mg per day, and 33% of 3600 mg per day is systemically absorbed.32 Gabapentin is often dosed 3 times a day, but anecdotally, absorption, and therefore analgesia, may be optimized if dosed 4 times per day instead. Pregabalin, on the other hand, can be dosed either 2 or 3 times a day.
Drug-drug interactions are minimal when compared with other medications. In small, dose-specific pharmacokinetic studies, coadministration of gabapentin with hydrocodone, morphine, or naproxen increased gabapentin absorption and, therefore, gabapentin blood concentration; clinical significance and the effect of other dosage combinations is unknown.3 According to the product information, the concurrent use of gabapentin with a combination aluminum and magnesium antacid may decrease gabapentin absorption by approximately 20%; therefore, gabapentin should be dosed 2 hours after use of this type of antacid.32 It is unknown whether this interaction is clinically significant.
In general, pregabalin is less cumbersome to use, and has more clinical trial data and an FDA approval to support its use in FM, but has not been on the market as long as gabapentin.3 Pregabalin is also more costly, is not yet available generically at the time of this writing, and is classed as a schedule V controlled substance. Of note, pregabalin or gabapentin can be added to a regimen consisting of antidepressants and/or opioids18; the concomitant use of pregabalin with gabapentin cannot be supported.
Other medications: Tramadol. There is little-to-no evidence to support the use of NSAIDs or opioids in FM.18,3 Some studies have reported benefit from the use of tramadol or tramadol/acetaminophen for pain management, but it is unclear if the benefit was clinically significant.18,30 The treatment of insomnia with sedative-hypnotics or the treatment of FM-associated anxiety or restless legs syndrome is beyond the scope of this article.
Tramadol is considered to be a nonnarcotic medication and at the time of this writing, is not classed as a controlled substance in most (but not all) states.30 It is interesting to note that the manufacturer’s information describes it as a centrally-acting synthetic opioid analgesic possessing a documented withdrawal syndrome associated with abrupt discontinuation.34 Its mechanism of action is twofold: The parent drug is a weak mu receptor agonist similar to the opioids, and its active metabolite blocks the reuptake of norepinephrine and 5HT.34
Tramadol may be an option to a stronger opioid; however, its side-effect profile in older adults may be cause for concern. Side effects include cognitive changes, constipation, dizziness, nausea, and orthostasis, and it is associated with seizures in patients with pre-existing seizure disorders.34 In patients who have never experienced a seizure, the seizure risk may be increased with concurrent use of tramadol and medications that decrease the seizure threshold, such as SSRIs, TCAs, opioids, monoamine oxidase inhibitors, and/or antipsychotics, and in patients taking higher than recommended tramadol doses.34 Because tramadol acts like a SNRI, it increases central serotonin concentrations and is implicated in causing serotonin syndrome in combination with other serotonergic medications (including but not limited to lithium, trazodone, SSRIs, SNRIs, St. John’s wort, TCAs, triptans, and CYP2D6 and 3A4 inhibitors). Use of tramadol with inhibitors of CYP2D6 (eg, amitriptyline, fluoxetine, paroxetine) or CYP3A4 (eg, azole antifungals, erythromycin, grapefruit juice) may limit the metabolism of tramadol and increase the risk of side effects, including serotonin syndrome and seizures.34
Use tramadol with caution in older adults, especially those over 75 years of age,34 titrating the dose slowly to a maximum of 300 mg per day.34 In addition, tramadol should be further dose-adjusted in patients with renal and/or hepatic insufficiency.34
Myofascial Pain Syndrome
Myofascial pain syndrome (MPS) is defined by the presence of trigger points in specific muscle regions of the body that produce a characteristic pattern of referred pain on palpation. The pathogenesis of MPS is unknown. Risk factors for MPS include degenerative joint disease, acute or repetitive trauma, postural problems, deconditioning, and sedentary lifestyle. Patients often report deep, boring pain localized in a specific muscular region of the body, usually involving the neck, shoulder, lower back, or hip region. One feature that differentiates MPS from FM is the presence of just one or a regional clustering of points in MPS in contrast to the widespread distribution of symptoms and tender points in patients with FM. Multiple clinical syndromes in different anatomic areas have been described in MPS.
The diagnosis of MPS is clinical. Examination of the patient with MPS reveals tender points in the affected areas that reproduce the regional pain and might produce a twitch response when pressed. There are no laboratory abnormalities characteristic of MPS. Treatment involves use of analgesic medications, trigger point injections with lidocaine, and stretching and strengthening exercises. Attention should also be given to elimination of possible aggravating factors such as postural abnormalities, overuse, or repetitive injury to the affected areas. A small, open-label trial using lidocaine 5% patches in patients with moderate-to-severe MPS found overall improvement in pain intensity, activity, mood, and sleep.35 Of note, the patches were added to a pre-existing pain regimen in all 27 patients.35
Lidocaine is a sodium-channel blocker available in many dosage forms for use in many, often diverse, conditions. The lidocaine 5% patch is often first line for localized neuropathicpain26; it is FDA-approved for the treatment of postherpetic neuralgia. It may be initiated concurrently with an oral agent due to its prompt onset of effect and minimal side-effect profile. In general, systemic absorption is minimal if up to 3 patches are used over 12 hours (FDA-approved dosing regimen).26 Reports describe other dosing strategies in healthy, normal adults utilizing 4 patches for 3 days (18 hr on and 6 hr off) or 4 patches for 3 days (changed either every 12 or every 24 hr); lidocaine plasma concentrations were low and below those associated with adverse effects.21
Prolonged use may result in higher systemic absorption, cause localized skin irritation, or may hasten tachyphylaxis to the drug. One should assess skin integrity and body surface area when considering use of the patch. Systemic absorption may increase if placed on areas of thinned skin, open wounds, or large body surfaces. Post-marketing information includes reports of disorientation, confusion, somnolence, and dizziness.36 Topical lidocaine should be used cautiously, if at all, in patients concurrently taking Class I antiarrhythmics and in patients with severe hepatic impairment.26 Lidocaine is also available in a gel and a 5% ointment, but may not provide a similar duration of benefit when compared with the patch. The formulations are not necessarily interchangeable. There may be systemic absorption concerns with the gel and the ointment formulations; one should consider the total body surface area being covered, the frequency of application, and whether the area will be occluded by clothing.
Peripheral Vascular Disease
Peripheral vascular disease (PVD) is common among the elderly, as its incidence and prevalence increases with age. It is characterized by the occlusion of blood supply to the extremities by atherosclerotic plaques (atheroma). The risk factors for the development of peripheral arterial atherosclerosis include diabetes mellitus, hyperlipidemia, cigarette smoking, hypertension, polycythemia, family history, and homocysteinuria.37
The most common presentation of PVD is intermittent claudication, which is characterized by pain, tightness, or weakness of an extremity that occurs with walking and is relieved promptly by rest. The pain results from muscle ischemia and is frequently described by patients as a squeezing pain. Other symptoms may include numbness, paresthesias, and a sense of coldness in the affected extremity. Depending on the level of the arterial occlusion, pain can be present in the buttock and hip (aortoiliac occlusion), thigh (common femoral artery or iliac occlusion), upper two-thirds of the calf (superficial femoral artery), lower one-third of the calf (popliteal artery), and foot (tibial or peroneal artery). Pain at rest will occur with progression of the disease. Patients will report discomfort that occurs at night and involves the digits and forefoot. Partial relief is possible with the foot in the dependent position. Chronic tissue ischemia may also result in ischemic neuropathic pain, which can aggravate the ischemic resting pain. Ischemic ulcers and gangrene may occur with severe PVD.
A thorough history addressing the risk factors and a complete physical examination with special attention to the peripheral pulses are essential for an accurate diagnosis. The absence of peripheral pulses indicates the presence of PVD. The foot and limb inspection may reveal muscle atrophy, changes in the skin color or temperature, loss of hair, dry skin, and thickened toenails. Ulcers, gangrene, and peripheral neuropathy may be present when PVD is severe.
Doppler ultrasonography can be used to assess arterial patency. The Doppler measurement is also useful in evaluating arterial insufficiency by determining the arterial-brachial index (ABI). An ABI of higher than 0.90 is considered normal, an ABI of 0.40-0.90 suggests a degree of arterial obstruction often associated with claudication, and an ABI of below 0.4 represents advanced ischemia.37
A complete blood cell count, serum creatinine and urea nitrogen levels, and serum lipids (total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides) should be measured. If indicated by history, the presence of diabetes mellitus may be assessed with a fasting glucose, hemoglobin A1C, or oral glucose tolerance test.
The treatment of PVD involves aggressive atherosclerotic disease risk factor modification, antiplatelet therapy, and regular assessment of the severity of the symptoms.37 Revascularization surgery is reserved for patients with disabling claudication, ischemic rest pain, gangrene, and nonhealing ulcers.
Modification of atherosclerotic disease risk factors includes lifestyle modifications such as regular exercise programs and tobacco cessation. In addition, aggressive control of diabetes mellitus, dyslipidemia, and hypertension are mandatory.37 Foot ulcer prevention in patients with diabetes mellitus should be included in the treatment plan.
Antiplatelet agents (aspirin or clopidrogel) may be prescribed for patients with PVD. Other drugs (pentoxifylline and cilostazol) have been used for management of PVD.37 Pain control with opioid therapy is required in patients who experience resting pain with severe PVD. Antidepressants and anticonvulsants can be used to control neuropathic pain associated with PVD.
Nocturnal leg cramps frequently occur in middle-aged and elderly patients. They tend to occur during sleep, and are usually accompanied by palpable hardening of the calf muscles and involuntary contraction and plantar flexion of the foot or toes. They usually are relieved if the patient gets out of the bed and walks around.
Leg cramps can be associated with volume depletion and electrolyte disturbances (eg, diuretic use, hypokalemia), structural disorders (eg, flat feet, hypermobility syndrome), prolonged sitting and inappropriate leg position during sedentary activity, neurological disorders (eg, Parkinson’s disease, neuropathies, myopathies), metabolic diseases (eg, diabetes mellitus, hypoglycemia, alcoholism, hypothyroidism, hypocalcemia), and, the most common, idiopathic causes.
The diagnosis is made by clinical history and physical examination focusing on possible identifiable factors. Examination of the extremities in patients with idiopathic leg cramps is usually normal. Laboratory tests such as serum electrolytes, glucose, thyroid function test, and serum calcium may be ordered to rule out secondary causes of leg cramps.
Patients should be encouraged to stretch the calf muscles for several minutes before sleep to prevent nocturnal leg cramps; however, there are insufficient data to confidently support this practice.38 Stretching immediately after a cramp occurs usually relieves symptoms. Other interventions include a hot shower prior to retiring, ice massage, regular exercise for conditioning and stretching, increased hydration, avoidance of caffeine, and proper footwear. Metabolic disturbances (eg, diabetes, hypoglycemia, hypocalcemia) and electrolyte abnormalities (eg, hypokalemia) should be treated accordingly when associated with leg cramps.
Quinine was the drug of choice for managing painful nocturnal leg cramps of undetermined etiology, but the dose formulation used for leg cramps was taken off of the U.S. market by the FDA in 2007 due to its multiple drug interactions, association with thrombocytopenia, narrow therapeutic range, association with a potentially fatal hypersensitivity reaction, and potential to cause a fatal QT prolongation.39 Quinine appears to increase the refractory period of the skeletal muscle and decrease the excitability of the motor end plate to stimulation.40
Sodium-channel blockers such as carbamazepine or topical lidocaine may be beneficial, but the literature is scarce, and it is unlikely that topical lidocaine will penetrate deeply enough to be effective.4 Gabapentin has been successful in small numbers of patients.40 In their review, Miller et al40 reported benefit from verapamil, baclofen for motor neuron disease, and equivocal results from oral vitamin E, but also noted an almost 40-50% placebo response in several trials. Carbamazepine or phenytoin may be beneficial given as a small bedtime dose,40 though a risk-benefit assessment should be made as these medications are associated with multiple potential risks. Other agents (calcium supplements, diphenhydramine, chloroquine phosphate) have been used empirically for this condition, though due to its anticholinergic effects, the use of diphenhydramine in older adults is generally not recommended.40
Persistent pain is a common problem in older adults. Several conditions such as PMR, GCA, FM, MPS, PVD, and leg cramps are common in this population. Becoming familiar with the diagnosis and treatment of these conditions is essential for the geriatrics healthcare provider. The therapeutic approach should be individualized and should combine pharmacological and nonpharmacological interventions when appropriate. The treatment goals should include providing analgesia and minimizing side effects while optimizing functional status, quality of life, and healthcare utilization.
The authors report no relevant financial relationships.
Dr. Zaleon is Adjunct Clinical Assistant Professor, University of Michigan College of Pharmacy, Ann Arbor, and Clinical Pharmacy Specialist, VA Ann Arbor Healthcare System, MI; and Dr. Montagnini is Associate Professor of Internal Medicine, Division of Geriatric Medicine, University of Michigan, and Director, Palliative Care Program, VA Ann Arbor Healthcare System.
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