OH DOCTOR, I HURT
| ASSESSING AND MANAGING PAIN —Louis Kuritzky, MD, Clinical Assistant Professor of Community Health and
Family Medicine, University of Florida College of Medicine, Gainesville
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| Reasons for utilizing pain assessment: for comparison, to show patient that attention placed on pain, and to validate
pain; for gradation of pain (eg, nagging pain, distracting pain); can use pain scales or ask patient to map, by time of day,
appreciation of pain and average (to tailor therapy to meet patient’s needs); neuropathic pain—2 most common types
diabetic and postherpetic; also phantom limb pain, postpolio pain, trigeminal neuralgia, and complex regional pain syndrome
(or reflex sympathetic dystrophy)
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| Diabetic peripheral neuropathic pain (DPNP): if neuropathic pain suspected in diabetic patient, confirm neurologic
status with ≥1 tool (check sensation by using monofilament; check ankle jerk); if any tests abnormal, provisional diagnosis
DPNP; should first fix glucose; glucose control prevents progression of diabetic neuropathy; in United Kingdom Prospective
Diabetes Study (UKPDS), blood pressure (BP) control better at forestalling progression of neuropathy than glucose
control; patients not adequately informed about neuropathy (eg, in study of 8000 diabetics, most unaware of diabetic
neuropathy); diabetic neuropathy worse with sleep, at night, and with exercise; leads to ulcers, limb loss, and death; typical
symptoms include tingling, burning, sharp pain, and hypersensitivity to touch (considered positive symptoms); also
lose sense of self when walking (due to loss of proprioception and sensitivity to touch); appropriate test for
diagnosis—most textbooks recommend monofilament test; article in Diabetes Care recommends C-128 tuning fork
(best predictive factor); first test tuning fork on big toe; if patient feels tuning fork, ask him or her to respond when it
stops; vibration sense impaired if physician able to feel vibration after patient inidicates it has stopped; 3 grades of vibratory
strength with tuning fork (normal, impaired, and lost)
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| Treatment of DPNP: tighter glucose control to prevent progression; alpha lipoic acid (ALA)—shown to reverse neuropathy
(seen in 2 trials); nonnarcotic analgesic—eg, acetaminophen (eg, Tylenol; up to 4 g daily) for relief of pain; using
pain scores makes patients confident that their discomfort being acknowledged; pain scores also useful for
establishing baseline and evaluating changes (meaningful increment, ≥30%); opioids—require higher doses; 5 double-
blind trials show that opioids effective for pain relief, sleep improvement, and preferred by patients previously on tricyclic
antidepressants (TCAs); oxycodone—80 mg/day needed to improve neuropathic pain; not first choice because of
side-effect profile; 70% of people have nausea; constipation almost universal (unless on bowel regimen); oxymorphone
(eg, Opana) not better analgesic; codeine—no inherent analgesic effect, eg, metabolized to morphine through cytochrome
P450 (CYP450 ) 2D6 (CYP2D6) system; only 10% of codeine metabolized to morphine; paroxetine (eg, Paxil) and
fluoxetine (eg, Prozac) prototypic 2D6 blockers; case reports of ultrametabolizers for 2D6 system; oxymorphone—no
CYP450 interactions (metabolized through glucuronidation); no attenuation of effect (not necessary to increase dose);
more expensive; works faster than morphine; tramadol also effective; TCAs—shown in trials to reduce DPNP and neuralgia
through balanced reuptake of norepinephrine (NE) and serotonin; prototype of agents that block NE and serotonin;
selective serotonin reuptake inhibitors (SSRIs)—not better for depression but easier to take; venlafaxine (Effexor) and
duloxetine (Cymbalta) NE and serotonin reuptake inhibitors without any of receptor affinities associated with TCAs (ie,
no orthostatic hypotension or weight gain); dosing for TCAs—start small; any TCA acceptable; gabapentin—
appropriate; ≤3600 mg/day; goal 30% reduction from baseline pain score; limitations include sedation, dizziness, weight
gain, edema, nausea, and vomiting; effective, but achieving dose that provides symptom relief without side effects difficult;
pregabalin (Lyrica)—similar to gabapentin; effective on all neurotransmitters; in one trial, pain scores dropped
from 6.75 to 4 in 1 wk and stayed same for 8 wk; given tid (limiting factor for some patients); neuropathy microvascular
complication (affects vasa nervorum); duloxetine—also used for depression; in trials for DPNP, patients with depression
excluded (to isolate effect of pain modulation); in 1 wk, pain reduced dramatically; by 12 wk, most patients had 50%
reduction in pain with once-daily dosing; venlafaxine—not effective at low doses; at 3 wk, higher doses work (takes
higher doses to interrupt NE and serotonin); lidocaine transdermal system (patch)—2 double-blind randomized vehicle-controlled
trials showed participants obtained statistically significant pain relief; proarrhythmic at too high dose and
antiarrhythmic at low dose; level of lidocaine achieved with 4 patches for 24 hr only one-tenth level shown to have cardiac
effect; safe (dose not even sufficient to cause anesthesia of skin); works as sodium channel blocker; can be cut into
smaller pieces; minimal side effects; in trial of DPNP, baseline pain (pain score ≈6.5) reduced by 30% at 3 wk; placed on
area of most intense pain; 5% lidocaine jelly not safe for use; increased sensitivity systemic effect; absorption minimally
systemic; theorized that impaired nitric oxide synthesis problem in DPNP; nitroglycerin—direct nitric oxide donor;
double-blind randomized placebo-controlled trial of nitroglycerin sprayed once in evening on painful area showed >30%
reduction in pain; participants reported analgesic effect lasting until next day; some able to exercise better; poorly absorbed
through skin
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| DEPRESSION WITH PAIN —Dr. Kuritzky
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| Overview: depression should be treated because suicide one of top 10 causes of death for last 15 yr; pain not in criteria for
diagnosis of depression (speaker terms “depressalgia”); data on 1100 patients who underwent screening before seeing clinician
show that if patient presents with pain, clinician more likely to miss depression than when patient admits to psychosocial
symptoms; presence of pain has high predictive value; pain commonly complicates depression (bilaterally
comorbid); if pain not controlled in depressed individual, depression does not get better; not all antidepressants work well
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| Pain and chronic depression: 3 studies of >500 participants; 50% to 60% had abnormal pain scores when they presented
with major depressive syndrome, not with any pain syndrome; another study showed that of 19,000 individuals screened,
700 met criteria for depression; of 700, 43% had painful physical condition that persisted for ≥6 mo; 32% had medical
condition that could cause pain; of 43% who had pain, only 14% had medical condition known to cause pain; when 600
patients with major depression asked about presence of pain, 65% answered positively when depressed (often chief complaint);
in international study of 1200 patients with depression, 69% of patients had pain as only complaint when they
presented to clinician; goal for patients with depression score of <7 on Hamilton Depression Rating Scale (HAM-D;
(qualifies as remission; in nondepressed healthy individuals, mean HAM-D score ≈2 [10-32 in depressed individuals]); if
patients have pain when they present with depression, neither pain nor depression likely to get better
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| Effect of pain on clinical course: time to remission—in patients given imipramine (Tofranil) with psychotherapy for
depression, time to remission ≈12 wk for patients without pain and 17 wk for those with pain; pain with depression also
predicts time to relapse; in general, 80% of patients with depression (if not treated) have second episode sometime in life;
in patients without pain who were asymptomatic, median time to relapse 231 wk; if residual pain symptoms present,
shorter time to relapse; conclusion—when pain not addressed, depression takes more time to improve, and patient more
likely to relapse; pain literature states that patients with chronic pain feel markedly better and able to resume normal
function if pain reduced by 50%; study—of patients with depression and painful symptoms, twice as many went into full
remission if their pain scores improved by >50% than if their scores improved by <50%
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| Addressing pain comorbid with depression: first discuss with patient; in study of top 10 problems patients find embarrassing
to talk about, depression at top of list; address balanced reuptake of serotonin and NE; when combined, serotonin and NE
“pain-damping”; SSRIs excellent depression medicines, but need balanced serotonin and NE to affect pain; nonspecific depressive
symptoms (eg, fatigue, anxiety, anhedonia) highly affected by SSRIs; minimal impact on painful physical symptoms; amitriptyline
and desipramine—interrupt NE and serotonin; have statistically significant benefit over placebo (fluoxetine does
not); venlafaxine—one of agents that modulate serotonin and NE; need high dose (serotonergic at low dose; at higher doses,
becomes more norepinephrinergic); at low doses, no tachycardia and BP changes; data show that in patients with neuropathic
pain, after 6 wk, pain scores reduced with high doses of venlafaxine; venlafaxine at low dose no different from placebo;
duloxetine— serotonin and NE reuptake inhibitor; similar to venlafaxine; within 2 wk, see dramatic reduction in pain that persists
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| CHRONIC PAIN MEDICATIONS —Donald R. Taylor, MD, Medical Director, Comprehensive Pain Care PC, Marietta,
GA
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| Polypharmacy: target drugs to different signaling pathways; different receptors targeted with drugs (eg, clonidine attacks
á-2 adrenergic receptors); midazolam—γ-aminobutyric acid (GABA) agonist; has analgesic activity; look for multimodal
synergism between drugs
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| Nonsteroidal anti-inflammatory drugs (NSAIDs): excellent drugs for rheumatoid arthritis; prescribed less often than
previously; work on cyclooxygenase (COX) enzyme; block prostaglandin synthesis (making them anti-inflammatory, antipyretic,
and analgesic); change blood flow in gastrointestinal (GI) tract, leading to ulcers; also affect blood flow in kidneys,
leading to renal failure; central effect reduction of nociception in thalamus; unclear to speaker whether drugs should
be given long term; COX-2 drugs—eg, celecoxib (Celebrex); still some risk for GI toxicity; also affect kidneys; effective
for dental pain; also used postoperatively (particularly celecoxib) to reduce need for narcotics; excellent for metastatic
bone pain; these medications cause ≈16,000 to 17,000 deaths annually; recent study shows 81 mg of aspirin daily
right dose to improve lifespan, due to its cardioprotective effects from inhibition of platelet function; at higher dose, risk
for side effects may negate cardioprotective effects
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| Acetaminophen: study shows giving cannabinoid blocker blocks analgesic effects of acetaminophen; possibly first cannabinoid
receptor agonist on market; number one drug of overdose deaths in Europe; affects liver
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| Antidepressants: useful for chronic pain; have analgesic efficacy; drugs that block NE uptake more effective than those
that block serotonin uptake; some data suggest that mixed NE and serotonin drugs more effective than pure NE drugs;
TCAs—block NE and serotonin reuptake; have N-methyl-D-aspartate acid (NMDA) receptor effects; have sodium ion
channel effects; á-adrenergic blockers; calcium channel blockers; work at mu receptor to enhance mu agonist function;
antihistaminic (doxepin 100 times more potent than diphenhydramine [Benadryl]) given topically or orally; side effects
include cardiac problems; not as safe as SSRIs in cardiac patients; can be used in elderly patients; nortriptyline in low
doses well tolerated in elderly (also effective as appetite stimulant); venlafaxine and duloxetine—as effective as TCAs,
with fewer side effects; serotonin-norepinephrine reuptake inhibitors (SNRIs); replacing TCAs in practice; bupropion
used as add-on drug when response from other drugs inadequate; preferred over TCAs because of lower toxicity; with antidepressants,
number needed to treat (NNT) for ≥50% reduction in pain (compared to placebo) for diabetic neuropathy,
≈3 (not very effective); 30% of patients obtain pain relief and 30% have minor adverse reactions; some patients unable to
tolerate TCAs at higher doses; fluoxetine—better tolerated but much less effective for analgesia; fewer side effects; suitable
for treating depression in patients with chronic pain; some patients may feel better when drugs discontinued
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| Anticonvulsants: suppress discharges in pathologically damaged or injured neurons; ideal for lancinating pain; also for
prickly, burning, or stinging pain; different agents have different mechanisms of action (can mix agents); most have multiple
mechanisms of action (eg, block sodium channel, block calcium channel, work at GABA receptor, inhibit glutamate
release); side effects limit dose; cognitive impairment often seen with use; also somnolence, word-finding issues (particularly
with [Topamax]), weight gain, edema, and hair loss; ≈30% of patients obtain satisfactory response; sodium channel
blockers—include carbamazepine (Tegretol), oxcarbazepine (Trileptal), and phenytoin (Dilantin); topiramate also
has some effect; in overweight diabetic patient with peripheral neuropathy, topiramate and zonisamide (Zonegran) first
choice, due to weight loss effect; in thin patients or those with eating disorders, gabapentin (Neurontin) or pregabalin recommended
because of association with weight gain
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| Antiarrhythmics: one of oldest treatments for neuropathic pain; primarily sodium channel blockers; reduce excitability of
neurons; block pain pathways without interfering with nerve function; decrease firing rates in neuromas, dorsal root ganglion,
and dorsal horn; thought antiallodynic and antihyperalgesic; intravenous (IV) lidocaine previously proposed as test
for neuropathic pain; available topically as Lidoderm patch; magnesium—blocks NMDA-regulated calcium channels;
in some studies, migraine shown to respond to IV magnesium; mexiletine—sodium channel blocker; may be better for
stabbing and burning pain
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| IV lidocaine: goal same plasma level as that obtained by cardiologist when using as antiarrhythmic; prepare to treat seizures
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| Calcium channel blockers: calcium channels—modulate nociceptive transmission at level of synapse; involved in
GABA, glutamate, and NE metabolism; in animals, blocking calcium channels reduces heat pain and mechanical pain;
N-type calcium channels—not same type in cardiac or smooth muscle; alpha 2-delta subunit specific site; blocking
leads to pain relief without affecting heart or blood vessels; N-type calcium-channel blockers include gabapentin, pregabalin,
and ziconotide; ziconotide—derived from Conus magus snail; first new intrathecal drug in 20 yr; indicated
when intrathecal morphine fails; no respiratory depression (even in massive overdoses) and no opiate effects; however,
has effects on brain and spinal cord; at high enough dose, can have psychiatric side effects (eg, paranoia, hallucinations;
avoid by slowly titrating)
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| GABA agonists: include gabatril, clonazepam, valproic acid, and baclofen (all used in treating pain); clonazepam benzodiazepine
and also used for treating seizures; gabatril and valproic acid antiepileptics; baclofen antispasmodic; help to
some degree with muscle spasm and neuropathic pain; diazepam one of most effective for muscle spasm (speaker tends
to avoid because of addiction problem)
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| Alpha-2 agonists: clonidine and tizanidine used for chronic pain of any type; nonspecific analgesics; also have sedative
and anxiolytic effects
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| NMDA receptor antagonists: include ketamine, memantine, methadone, dextromethorphan, and amantadine; memantine
(Namenda) for chronic refractory migraines; ketamine—potent analgesic; at higher doses, can produce psychomimetic
effects (catatonic trance-like state); used in operating room; related to phencyclidine (PCP)
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Suggested Reading
Argoff CE et al: Consensus guidelines: treatment planning and options. Diabetic peripheral neuropathic pain. Mayo Clin
Proc 81:S12, 2006; Buescher JJ: Carbamazepine for acute and chronic pain. Am Fam Physician 73:1549, 2006; Cayley
WE Jr: Antidepressants for the treatment of neuropathic pain. Am Fam Physician 73:1933, 2006; Cooper JA et al: Response
of intrathecal baclofen resistance to dose reduction. Neurology 67:1495, 2006; Forde G: Adjuvant analgesics for the
treatment of neuropathic pain: evaluating efficacy and safety profiles. J Fam Pract 56:3, 2007; Gajraj NM: Pregabalin: its
pharmacology and use in pain management. Anesth Analg 105:1805, 2007; Gilron I et al: Morphine, gabapentin, or their
combination for neuropathic pain. N Engl J Med 352:1324, 2005; Gilron I et al: Neuropathic pain: a practical guide for the
clinician. CMAJ 175:265, 2006; Horowitz SH: The diagnostic workup of patients with neuropathic pain. Med Clin North
Am 91:21, 2007; Kline KM et al: Painful diabetic peripheral neuropathy relieved with use of oral topiramate. South Med J
96:602, 2003; Leong IY et al: The relationship between medical comorbidity and self-rated pain, mood disturbance, and
function in older people with chronic pain. J Gerontol A Biol Sci Med Sci 62:550, 2007; Lesser H et al: Pregabalin relieves
symptoms of painful diabetic neuropathy: a randomized controlled trial. Neurology 63:2104, 2004; Maizels M et al: Antidepressants
and antiepileptic drugs for chronic non-cancer pain. Am Fam Physician 71:483, 2005; Raskin J et al: Efficacy of
duloxetine on cognition, depression, and pain in elderly patients with major depressive disorder: an 8-week, double-blind, placebo-controlled
trial. Am J Psychiatry 164:900, 2007; Sumner CJ et al: The spectrum of neuropathy in diabetes and impaired
glucose tolerance. Neurology 60:108, 2003.
Educational Objectives
| The goal of this program is to improve the management of pain, especially pain associated with diabetes and depression.
After hearing and assimilating this program, the clinician will be better able to:
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 | 1. Diagnose and treat diabetic peripheral neuropathic pain.
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| 2. Recognize the importance of treating pain in patients with depression.
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| 3. Prescribe appropriate drugs to treat pain comorbid with depression.
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| 4. Review the different classes of drugs used to treat chronic pain and their mechanisms of action.
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| 5. Utilize the appropriate drugs in patients with chronic pain.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and planning committee
members to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of
interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and
not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Kuritzky is on the
Speakers’ Bureaus for GlaxoSmithKline, Boehringer Ingelheim, Merck, Endo Pharmaceuticals, Pfizer, and Eli Lilly. Dr.
Taylor is on the Speakers’ Bureaus for Cephalon, Elan Corp, and Reckitt Benckiser Pharmaceuticals. The planning committee
reported nothing to disclose.
Acknowledgments
Dr. Kuritzky was recorded at 2007 Primary Care Update, held November 4-7, 2007, in Savannah, GA, sponsored by Interstate
Postgraduate Medical Education. Dr. Taylor was recorded at the Sixth Annual Augusta Pain and Headache Conference
, held May 18-19, 2007, in Augusta, GA, and sponsored by Walton Pain and Headache Centers at Walton
Rehabilitation System in conjunction with the Medical College of Georgia, Division of Continuing Education, and School
of Medicine. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of
this program.
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