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Chronic Pain

Maunak Rana and W. Scott Jellish


Chronic pain is pain that lasts longer than the usual time for a given disorder to heal.
The International Association for the Study of Pain defines chronic pain as pain
that is present for 3 months beyond an inciting event. The persistence of pain is a
serious health problem because it dramatically impacts the economic, physi- cal, and
bio-psychosocial well-being of society. This chapter presents a broad overview of the
classification and treatment of chronic painful states.
1. TYPES OF CHRONIC PAIN
The sensation of pain can be broadly classified into "neuropathic,
musculoskeletal, and psychological" types.
A. Neuropathic pain is described as "electric burning, or shock-like.
Sources of neuropathic pain can be metabolic, nutritional, in fectious,
genetic, autoimmune, and vasculitic processes. These problems can lead
to muscle cramps, numb- ness. and weakness of an affected extremity,
causing mononeuropa thy or polyneuropathy.
B. Musculoskeletal pain is described as aching" (superficial ordeep).
Discomfort is associated with muscle spasms and decreased range of
motion. lf persistent, pain may lead to disuse atrophy and contractures.
Causes include myofascial pain, fibromyalgia, posttraumatic/ iatrogenic,
myopathy, metabolic bone/ muscle disease, secondary to arthritis, and/ or
intervertebral disc disease.
C. Psychological pain may present as any of the above. Patients may also
describe difficulty sleeping, diminished physical, mental, and social
functions. Treatment involves addressing the problem with the patient and
acknmvledging that depression and anxiety may be part of the patients
chronic pain requiring treat- ment. Primary psychological derangement or
a secondary underlying cause of chronic pain may be the problem.]

II. MANAGEMENT OF CHRONIC PAIN


Precise diagnosis and implementation of treatment must occur in treating chronic
pain. Treatment may involve medication therapy, interventional options, and
biofeedback.

A. Medications.
1. Nonsteroidal anti-inflammatory drugs (NSAIDS). These agents are believed to
lead to analgesia via central and pe'fipheral mechanisms. They function through
the inhibition of the arachidonic acid cascade, leading to a decreased production
of prostaglandins. Patients may have varying reSponses to differ- ent agents in
this class. These agents can be classified based on activity of agent against
cyclooxygenase [/11 activity (COX). COX 1/ nonselective agents in- clude
ibuprofen, naproxen, and piroxicam. Celecoxib is currently the only COX 1]
selective agent available in the United States. Paracnxib, an intravenous COX [1
selective agent, is not currently available in the United States. Common side
effects of NSAIDs include renal dysfunction, gastrointestinal bleeding, and ulcer
formation. The antiplatelet effects are not seen in celecoxib and other COX ll
selective agents.
2. Opioids. These drugs are naturally occurring alkaloids or may be synthetically
produced. These agents Function to varying degrees at the opioid receptors. in the
central nervous system (CNS) and the periphery. These agents are classified based
on chemical structure. Opium plant derivatives (plienthrenel include morphine
and codeine. Agents that are synthetically derived from the phennnthrenes (semisynthetic) are hydrocodone, oxymorphone, and oxycodone. Synthetic agents not
derived from the phenanthrene; include the anilindopiperidincs, fentanyl
(transdermal. buccal, sublingual), 'sutentanil, reinitentnnil. 'l'he phenylpiperidines
are meperidine and tmtnadol; phenylpropylamines include propoxyphene,
methadone, and loperarnide. Pentazocine is a benzomorphane, oripavane
(buprenorphinel), and morphinan drugs include butorponal and nai- buphine.
Buprenorpiine is an opioid receptor agnnist.fanlngonist that has also been used in
pain management [Table 50.1].
Clinicians should utilize preparations w ith the least abuse potential and side
effects. Agents that contain an anti-inflammantory / acetaminopen to decrease the
dose of opioid required fox analgesia should be considered first-line drugs
Prescribing physicians should notifyp atients about the clinics prescription policy via the use of a "narcotics contract or narcotics agreement." Common side
effects include respiratmy depression, sedation, cognitive impairment livel dvsfunction, and testosterone deficiency in men both with long-term use Tolerence
addiction potential, and withdrawal from sudden cessation are also common.

3. Antidepressants. Antidepressants are also utilized in chronic pain management.


These agents act via various mechanisms including a direct antidepressant effect,
a decrease in synaptic transmission, and the enhancement of action of endogenous
opioids (Table 50.2). They are classified based on their mechanism of action.
Tricyclic antidepressants include amitriptyline and nortriptyline. Common side
effects of these agents include dry mouth, sedation, sexual dysfunction, hyponatremia, and the risk of withdrawal if abruptly discontinued. Selective serotonin
reuptake inhibitors (SSRI) are another class of antidepressant and include
uoxetine and duloxitene. Duloxetine is a dopamine, serotonin, and norepinephrine reupta ke inhibitor. This drug is used for diabetic neuropathy and contraindicated in patients with concomitant monoamine oxidase inhibitors (MAOIS)
therapy, hypersensitivity, and narrow angle glaucoma. Common side effects of
SSRI agents include dry mouth, constipation, orthostatic hypotension, weight
gain, dizziness, unmasking of mania in bipolar patients, and risk of seizure in
patients receiving tramadol. Other agents in this class include buproprion,
trazadone, and venlafaxine. Clinicians should be aware that lower doses of
antidepressants are used for analgesia than for antidepression.
4.

Anticonvulsants. Anticonvulsants are also used in the treatment of chronic


painful conditions. Many agents in this category have a common historical use for
the prevention and suppression of seizure disorders.These drugs act via different
mechanisms including increasing inhibitory neurotransmitters, decreasing
excitatory transmitters, and blocking ion channels. These agents are most
effective for neuropathic pain states, although medications of the other classes may
be utilized (Table 50.2).
Phenytoin is used to treat diabetic neuropathy. Treatment is initiated at 3th
mg per day, titrating upward as needed. Side effects include gingival hyperplasia,
hisrutism, acne, and coarsening of features. This agent activates the P450 enzyme
system in the liver, resulting in a decreased efficacy of mexile- tine, haloperidol,
and carbamazepine. Co-administration with antidepressants may lead to increased
blend levels of phenytoin.

table 50.1 Narcotic


Drugs
Starting dose
Morphine (avalaible in
immediate
refease 15-30 mg q 4 hr
continnous extended release, immediate release
clixir)
15-60 mg po q 4-6
Cademe
(availablein
hr, not to exceed
various combinations)
360 mg/24
Oxycodone (also available
with
acetaminophen- 10-30 mg q 4 hr
percocet)
Oxymorphone

1 mg IV q 4-6 hr

Goal dose

Side effect

use
preparation
with least abuse respirotary distress
potential
sedative,
cognitive
impairment
use
combination
agent that contain
an
anti liver dysfunction with
inflammatory
to long-term use
decrease
opioid
dose
testosterone
deficiency

Hydrocodone
(available 1 tablet q 4-6, not
with
acetaminophen to exceed 3-4 g of
norco, vicodin, lorbab), acetaninophen qd
addiction potential
Available with inbuprofenvicoprofen)
patch: start @ 25 may
utilize
withdrawal
with
Fentanyl
meg/q72 hr
narcotic contract to
cessation
control abuse
15-35 mg/hr IV
Meperidine
50-100 mg po qid,
max 400 g/qd; if
Tramadol (also available in
>75 yrs, hepatic or
combination
with
renal dysfunction,
acetaminophen)
max daily dose 200
mg/qd
65 mg q 4 hr
Propoxyphene
2,5 mg to 10 mg q
Methadone & loparemide
8-12 hr
Pentazocin in formullation 1 tablet q 4hr PRN
with aspirin and/or naloxone
Buprenorphine
(also variable
with
available in formulation formulation
with naloxone)
1 mg to 4 mg q 3-4
Butorphanole
hr by MDI

Nalbuphinc

10 mg/70 kg body
wt 3-4 hrs PRN.
Total daily dose <
160 mg/qd

Table 50.2 Non-Narcotic Drugs


Drugs
Use
Amitriptyhine
neuropatic pain

Nortiptyline

Duloxetine

diabetic
neuropatic pain

Starting dose

Goal dose

50 mg qhs

150 mg qhs

25 mg pq qhs

150 mg qhs

60 mg qd

120 mg qd

300 mg/day
Phenytoin

Carbamazepine

Lamotrigine

Topiramate

Levetiracetam

diabetic
neuropatic
trigelminal
100 mg BID
neuralgia,
post
stroke pain, post
herpetic
neuralgia,
neuropathy
20-50 mg po qHS
cold-induced
pain, trigeminal
neuralgia,
neuropathy
diabetic
50 mg qHS
neurophaty, post
herpetic
neuralgia,
intercostal
neuralgia, CRPS
500 mg po bid

300-400
mg/day
300-1,000
mg/day
in
divided bid
doses over 2
wks

Side effect
Sedation,
dry
mounth,
impotenci,
hyponia thermia,
withdrawal
Dry
mputh
constipation,
orthostatic
hypotension,weig
ht gain, dizziness,
unmasking
of
mania in bipolar
patients
on
tramadol
gingival
hyperplasia,
hirsutism,
coarsening
of
features.
gait disturbances,
hyponatremia,
neucopenia,
aplastic anemia,
agranulocytosis.

rash,
stevens300-500
jhonson syndrom,
mg/day
in decreased efficacy
divided bid with
codoses over 2 administration or
wks
carbamazepine,
phenytoin
sedation, kidney
200 mg po
stone,
ocular
bid
granuloma
1,500 mg bid

rash,

hives,

100 -300 mg qHS


Gabapentin

neuropatic pain

pregabalin

diabetic
neurophaty, post
herpetic
neuralgia, CRPS

150 mg/day

100 mg/day
Zonisamide

neuropatic pain
0-3-1 nanograms/hr

Conopeptide

cancer pain, hiv


neurophathy

Baelofen

spinal cord injury,


spaticty

5 mg dd

4 mg qd
Tiagabine

neuropatic
spaticty

pain,

Diazepam

Tizanidine
Cyclobenzaorin
e
Chlorzoxasone

muscle spasms,
spaticty
2 mg bid
muscle spasms,
spaticty,
spinal
cord
injurypost
troke pain
4 mg/qd
muscle spasms
muscle spasms

30-40 mg/qd
250 mg tid/qid

4,800 mg po
divided
in
TID dosing
600 mg/day
for
neurophatic
pain;
450
mg/day for
fibromyalgia

itching, dizziness
fatigue,
somnolence,
dizziness
dizziness, blurred
vison,
weight
gain, diminished
cognition

ataxia,
rash,
kidney
stones,
600 mg/day
oligohydramnios,
pediatric
hyperthermia
sedation, tremor,
hypotension,
histaminergic
reaction
confusion, ataxia,
80-100
hallucination,
mg/day
in
lifetheatring
devided doses
withdrawal
12-22 mg/qd
for pts not on
epilepsi drugs seizures, aphasia,
32-53 mg/qp sedation
for pts on
AEDs
sedation,
dependence, risk
of seizures and
deadth
with
20-30 mg/qd withdrawal
increase by 4- headache,
6 mg/wk to digestive change,
36 mg/mq
dry mouth
sedation,
dry
30-40 mg/qd mouth
1,000-2,000
GI disturbances,
mg/qd
liver dysfuntion,

Carisoprodol
methucarbomol

muscle
spasms,spaticty

350 mg tid/qid

muscle spasms

1000 mg/tid

muscle spasms

800 mg tid/qid

Metaxolone

Orphenadrine
neuropathic,muscl
e spasms
60-80 mg q 8 hrs
Dystonia,
spaticity,
migraine,
botulinum toxin
torticallis,
myofascial pain, varies base on site of
GI, GU spam
injection

sedation
sedation, tremor,
350 mg po altred cognition,
tid/qid
addiction potential
3000-4000
sedation, altered
mg/qid
cognition
hemolytic anemia,
800
mg elevated
liver
tid/qid
function test
ortbostic
hypotension,
urinary retention,
60-80 mg q 8 dizziness,
hrs
euphoria

myalgia,
dysphagia,
discomfort

Carbama/epine is used for trigeminal neuralgia (tic douloureux), post-stroke pain,


post-herpetic neuralgia, and diabetic neuropathy. The drug 18 believed to act vi:
central and peripheral mechanisms, selectively targeting actively firing C and A delta
fibers. T1 eatment is started at 100 mg twice a day and titrated to effect. The typical
dose range is 300 to 1,000 mg/d in divided doses. Side effects include gait alterations,
hyponatremia, lenkopenia, aplastic anemia, and agran ulocytosis. As a result of
these potential hematologic alterations, blood tests are recommended every 2 to 4
months Oxcarbazepine is an analogue of carba- mazepine less likely to cause CNS/
blood alterations. Side effects include hyponatremia (sodium of less than 125 mmol/
L), sedation, and dizziness.
Lamotrigine prevents the release of glutamate in addition to blocking active
sodium channels. This agent is used for cold-induced discomfort, trigeminal
neuralgia, and diabetic and HIV neuropathy. The starting dose is 20 to 50 mg at
bedtime, slowly increased to 300 to 500 mg per day in twice daily divided doses
(over 2 weeks). A rash, the most common side effect, is commonly seen in pediatric
patients, patients receiving valproic acid, and in patients receiving rapid titration of
lamictal. The rash may also lead to StevensJohnson syn- drome. Clinicians should
note a decreased efficacy of lamotrigine with con- comitant administration of
carbamazepine and phenytoin.
Topiraniate acts at both sodium channels and calcium channels, enhanc ing
the action of GABA, and inhibiting AMPA glutamate receptors. The agent is used in
diabetic neuropathy, post-herpetic neuralgia, intercostal neuralgia, and complex
regional pain syndrome (CRPS) (see Chapter 51). Dosing is be gun at 50 mg at
bedtime, increasing to 200 mg twice daily. Side effects include sedation, development
of kidney stones, and ocular granuloma due to inhibi- tion of carbonic anhydrase. A
final channel blocking agent, levetiracetam is started at 500 mg by mouth twice daily
and adjusted to a target of 1,500 mg twice a day. Side effects include a rash, hives,
itching, and dizziness.
5. Local anesthetics: Lidocaine is available in salve and patch (5%) forms. It is used for
post-herpetic neuralgia, postthoractomy pain, intercostal neuralgia, and
fibromyalgia. The drug is started at l to 5 mg/kg intravenously. The patch is used for
12 hours per day and may be cut to size and shape. Side effects of lidocaine include
bradycardia, dizziness (at plasma level of 10 mg/mL), cardiac depression (at 20 to 25
mg/mL plasma level), blurred Vision, and seizure. Mexiletine, an oral analogue of
lidocaine, is used for post-stroke pain, myoto- nia, spasticity, and diabetic neuropathy.

Treatment is initiated at 150 mg/d up to a goal of 300 to 450 mg/d. The side effect
profile is similar to lidocaine.
6. Calcium channel blockers. Gabapentin is a membrane stabilizer binding at the
alpha-2 delta subunit of the L-calcium channel (Table 50.2). The name of the drug is
a misnomer as gabapentin has no activity at the GABA receptor but is struc- turally
similar. Gabapentin is used for many neuropathic pain states including diabetic
neuropathy, postherpetic neuralgia, and CRPS. Treatment is started at 100 to 300
mg at bedtime, increasing to 4,800 mg per day divided in three times a day dosing.
Common side effects include fatigue, somnolence, and dizziness. Pregabalin also
binds to the alpha-2-delta subunit at voltage-dependent calcium channels. This agent
is used for neuropathic pain states and for fi- bromyalgia. The starting dose of
pregabalin is 150 mg/d titrated to 600 mg/ d for neuropathic pain states; for
fibromyalgia the maximum daily dose is 450 mg/d. Side effects include dizziness,
blurred vision, weight gain, and diminished cognition.
Zonisamide acts at T- calcium and sodium channels.This drug in GABA
release. Zonisamide is started at 100 mg every day and increase 2 weeks by 200 m
g/Wk for a goal of 600 mg/ d. Common side effects 1 ataxia, rash, kidnegy stones
(carbonic anhychase inhibitor), oligohydia and pediatric hyperthermia.
-Couopeptides (ziconotide) acts on N-type calcium channels. Use trathecally
at 0.3 to 1 nanograms/ kg/ hr. The drug has been studied in
and HIV populations. Side effects include sedation, tremor, hypotension, and
histaminergic reaction. Nimodipine, diltiazem, verapamil, and nifedipine are agents
typically used for blood pressure control but may also have a role with other agents in
pain management. .
7. Gabaergic agents. Baclofeii is a derivative of GABA With activity at GABA-b
channels. It has both spinal and supraspinal activity (Table 50.2). This drug is used
For spinal cord injury and spasticity. Initial therapy begins at 5 mg three times a day
with titration to a daily dose of 80 to 100 mg/d. Baclofen may also be given
intrathecally. Common side effects include confusion, ataxia, and hal- lucinations.
Sudden cessation of therapy may lead to a withdrawal, which may be life-threatening.
Tiagabine acts as a GABA reuptake inhibitor. The drug is started at 4 mg daily
and increased by 4 to 8 mg/d to a final goal of 12 to 22 mg/d for patients not on
antiepileptic drugs (AED), or 32 to 52 mg/d for patients on AEDs. Common side

effects include risk of seizures in patients without a history of seizure disorder,


aphasia, and sedation.
The benzodiazepine Diazepam is a muscle relaxant that enhances the
inhibitory action of GABA-A receptors used in patients with spinal cord dis- ease and
muscle spasms. Diazepam is usually started at 2 mg twice daily to a total dose of 20
to 30 mg/d. Side effects include sedation and dependence. A withdrawal with sudden
cessation may lead to seizures and death.
8. Muscle relaxants. Tizanidine is a centrally active alpha 2 adrenergic agc for
spasticity, spinal cord injuiy, and post-stroke pain (Table 50.2). Dos at 4 mg/d and is
increased by 4 to 6 mg/wk to a total of 36 mg/d. Si include headache, digestive
changes, and diy mouth. Clinicians shoulc caution with concomitant use of other
alpha 2 agonist agents because c of hypotension. Cyclobenzaprine is a muscle
relaxant that primarily abrainstem, although it is not effective for centrally mediated
spastic states The dose is 30 to 40 mg/d and side effects include sedation and dry
mouth
Chlorzoxazone is centrally acting with a target dose of 1,000 to 2,000 mg/d.
Side effects include Cl disturbances, sedation, and liver dysfunction. Carisoprodol is
a muscle relaxant that acts centrally at the reticular activating system and the spinal
cord. The treatment goal is 350 mg three to four times a day. Side effects include
sedation, tremor, altered cognition, and a risk for addiction potential. Methocarbainol
is used at 3,000 to 4,000 mg/ d. Metaxolone is dosed at 800 mg three to four times a
day. This drug may lead to hemolytic anemia and elevated liver function tests.
Orphenad rine is an NMDA antagonist with anticholinergic effects. It acts via
central and peripheral mechanisms. This drug is used fcir neuropathic pain and
muscle spasms. It potentiates the analgesic effects of opioids. Orphenadrine is started
at 60 to 80 mg q 8 hours. Side effects include orthostatic hypotension, urinary
retention, dizziness, and euphoria.
Botulinum toxin is a muscle relaxant that acts at the neuromuscular junc
tion and inhibits the release of acetylcholine presynaptically. Its effect lasts for
approximately 3 months. This agent is used for dystonia (writers cramp, musicians
cramp), spasticity, migraine headaches, hyperhidrosis, myofas- cial pain, and
gastrointestinal and genitourinary spasm. It should not be used in patients with
neuromuscular junction / motor neuron dysfunction such as myasthenia gravis,
LambertEaton myasthenic syndrome (LEMS), and amy otrophic lateral sclerosis

(ALS). Side effects include myalgia, dysphagia, and local discomfort. The amount of
agent on injection is tailored to the site of injection with attention to the degree of
spasm and the musculature being injected.
9. Other agents. Clonidine is an alpha 2 agonist that potentiates the analgesic action of
Opioids. It is useful in neuropathic pain states. A transdermal patch is started at a dose
of 0.1 mg/d changed every 7 days. Side effects include sedation, dry mouth, and
orthostatic hypotension. Capsaicin is an extract of chili pepper, which is thought to
cause analgesia by depletion of substance P. Clinicians should note that application
may lead to discomfort and irritation prior to analgesia.
B. Nonpharmacologic treatments.
1. physical therapy and occupational therapy. The use at heal, ultrasound, electrical
stimulation, and deep tissue massage may reduce discount. chronic pain states.
Additionally, in neurepathic pain states, targeting different fibers can lead to
decreasing the hypersensitivity (allodynia) that may be present as part of a painful
condition. The mainstay of treatment of certain conditions, including CRPS, is range
of motion and physical therapy. Prevention of contracture is important in maintaining
function and decreasing discomfort.
2. Electrical stimulation involves the use or eitner transcutaneous electrical nerve,
stimulation (TENS), spinal cord (dorsal column), or thalamic stimulators, which
can modulate pain. Patients with neuropathic pain states, muscular pain, central pain,
and axial low back pain may benefit from these therapies. The classical "gate control
theory in that stimulation of large fiber (a beta) closes the gate that has been opened
or initiated by the smaller diameter nociceptors. Contraindications for these therapies
include pregnancy and the presence of a pacemaker. I II . .- -L:.-.li.~ .xunxr
3. Psychological treatment is an important component or me pauem s mum. chronic p.
in treatment plan by addressing the psychological manifestations of the pain. A
support network for the patient involving family and friends may be conducive to the
healing process. Additionally, the use of biofeed- back along with adjunctive physical
therapy may help a patient cope with their discomfort.
Finally, the ultimate goal in the management or a patient with cronic pain is a
precise diagnosis with appropriate treatment for the painful condition. Referral to an
interventional pain physician may benefit the patient after conservative therapy has
failed. With the advent of technological advances, disease processes difficult to treat,

such as complex regional pain syndrome, diabetic neuropathy, and peripheral


neuropathies, may be addressed with a specialist versed in providing interventional
modalities along with pharmacotherapy. Physical therapy is also a vital component of
the patients health in decreasing discomfort. As the primary care provider, it is
crucial to have an honest communication with the patient about treatment goals,
expectations, and the possibility of achieving those expectations.

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