Pain Management Part II: PharmacologicManagement of Chronic Orofacial Pain
Steven Ganzberg, DMD, MSProfessor of Clinical Anesthesiology, College of Dentistry, College of Medicine & Public Health, Dental/Maxillofacial Anesthesiology ResidencyProgram Director, The Ohio State University
The pharmacologic management of chronic orofacial pain involves the use ofmedications not used routinely in dental practice. Additionally, many drugs areused for long periods of time necessitating careful monitoring for adverse effectsand potential drug interactions. This article will review commonly used medica-tions for chronic orofacial pain and highlight important areas of concern.
Key Words: Chronic pain; Orofacial pain; Pain management.
Chronic orofacial pain (COP) comprises a hetero- should be noted that there are many sources of chron-
geneous group of disorders that cause ongoing
ic orofacial painsöfor example, those that arise from
pain in the head and face region. Although there are
ocular, salivary gland, nasal mucosal and intracranial
many proposed taxonomies, one system divides these
lesions; even from lung cancer. Many of these condi-
pains into musculoskeletal, neuropathic, and neuro-
tions are not usually treated by the dentist, but the
vascular pains. Psychogenic pains comprise yet an-
dentist treating orofacial pain must be familiar with
other category, but true psychogenic pains, such as
the wide range of differential diagnoses for any given
those associated with conversion disorder or schizo-
phrenia, are so rare that their management will notbe addressed in this article.
Musculoskeletal pains consist of temporomandibu-
lar joint disorders and masticatory muscular disordersbut also include a variety of cervical conditions which
The management of COP differs significantly from
refer pain to the head and face, such as cervical myo-
that of acute pain. Although all pain has both
fascial syndromes and cervical facet arthropathies.
sensory- discriminative (nociceptive) and motivational-
Neuropathic pains involve those with damage or alter-
affective (psychological) components affecting overall
ation to peripheral or central pain pathways; the most
perception, chronic pain frequently has significant ef-
well known of these is trigeminal neuralgia, but post-
fects on psychological health and, in turn, the patient’s
traumatic neuropathies are also quite common. Sym-
ability to cope with daily pain. Depression and anxiety
pathetically mediated pains, such as complexregional
are common and can profoundly affect pain percep-
pain syndrome, Type 1, are also known to occur in the
tion; hence, the use of psychotropic medication is
face. Many nonodontogenic toothaches are, in fact,
common. This article will review pharmacologic man-
neuropathic painsöeither atypical forms of trigeminal
agement of chronic pain, but the reader should not
neuralgia or so-called deafferentation pains associated
presume that medication management is the primary
with alteration in pain transduction, transmission, or
treatment modality. For many patients who suffer with
modulation. Common neurovascular pains include mi-
chronic pain, psychological therapies are at least as,
graine, tension-type headache, cluster headache, and
and sometimes more, important than sound pharma-
the numerous variants associated with each of these
cologic and interventional measures.
headaches. Because of the wide variety of conditions,
Many different medication classes are commonly
many different medication classes are utilized. It
used as analgesics for chronic pains versus acute pain. These include antidepressants, particularly the tricy-clic antidepressants ( TCAs)1,2 and the selective seroto-
Received June 15, 2010; accepted for publication June 21, 2010. Address correspondence to Dr Ganzberg at ganzberg.1@osu.edu.
nin-norepinephrine reuptake inhibitors ( SNRIs),3^5
E 2010 by the American Dental Society of Anesthesiology
nonsteroidal anti-inflammatory agents ( NSAIDs) when
teractions. These include loss of hypertension control
an inflammatory component is present, and the
with any antihypertensive, due in part to NSAID-in-
opioids. The latter 2 groups were discussed in the pre-
duced decreased renal blood flow and increased renin
vious article, ‘ Pain Management: Part I: Managing
release. Renal toxicity is of particular concern in patients
Acute and Postoperative Dental Pain.’ 6 Only relevant
taking angiotensin-converting enzyme ( ACE ) inhibitors,
issues associated with the use of these medications in
angiotensin receptor blockers, and beta blockers because
chronic pain versus acute pain will be highlighted in
the combination of NSAIDs and these agents can cause
loss of renal blood flow autoregulation. Patients with con-
In addition to these agents, the anti-epileptic drugs
gestive heart failure who are using these medications are
( AEDs) are also very commonly used for neuropathic
particularly at risk. Those taking sulfonylurea oral hypo-
and neurovascular pains.7 The muscle relaxants are
glycemic agents may have increased free plasma drug
not as useful in chronic as in acute musculoskeletal
concentration, with resultant hypoglycemia, when
pain,8 although the antispastics, a different group in-
NSAIDs, which are highly plasma protein bound, are
cluding baclofen and tizanidine, show utility in a num-
used long term. Of course, warfarin (Coumadin) and tra-
ber of disorders. The various primary headaches utilize
ditional NSAIDs should not be prescribed concomitantly.
a wide array of medications from many classes in ad-
Toxicity with methotrexate, as used for many autoim-
dition to those above: beta blockers, calcium channel
mune conditions, and lithium salts, as used for bipolar
blockers, lithium, ‘ triptans,’ ergots, and others.
disorder or cluster headache, can occur when NSAIDs
In regard to dosing for COP, medications should be
are prescribed with these agents. Interestingly, of all the
prescribed on a time contingent basis and, if appropri-
drugs used for COP, NSAIDs are some of the most con-
ate, medications with longer dosing intervals are pref-
cerning when used for long periods of time.
erable. The need for patients to take medicationsfrequently during the day, as well as on an as-needed
basis, reinforces pain behaviors in some individuals. Compliance is a much more complicated issue in
Opioids have been used for the management of pain
COP versus acute pain mentioned in the previous
for centuries, and the pharmacology of these agents
was also discussed in Part I of this series. There is lesscontroversy today over the use of opioids for chronicpain than in the past.9,10 Nevertheless, there are rea-
sons that long-term opioids are not appropriate for
many patients with chronic pain, but that discussionis beyond the scope of this article. When used, long-
NSAIDs are most commonly used for musculoskeletal
COP, such as temporomandibular joint disorders and
agents, such as morphine ( MS Contin, Oramorph SR,
myofascial syndromes. Part I of this series discussed
Avinza, Kadian), oxycodone ( OxyContin), oxymor-
NSAID pharmacology. As opposed to acute pain phar-
phone ( Opana), methadone, and levorphanol are pre-
macotherapy, when any medication is used on a long-
ferred. The latter 2 agents have N-methyl-D-aspartate
term basis as for many chronic pain conditions, the
( NMDA ) blocking effects as well. Fentanyl transdermal
risk of adverse effects increases and monitoring be-
patches are also available. Short-acting agents can be
comes more essential. Long-term NSAID use requires
considered for breakthrough pain but only when clear
laboratory monitoring for GI bleeding, adverse renal
indications exist. It can be challenging, however, for
effects, and possible hepatic effects. An initial com-
even the most experienced clinician to distinguish be-
plete blood count and chemistry to include at least
tween tolerance and exacerbation of the existing pain
blood urea nitrogen and creatinine blood levels are
condition. It must be remembered that the use of com-
useful, but baseline aspartate aminotransferase ( AST )
bination opioids (eg, hydrocodone or oxycodone with
and alanine aminotransferase ( ALT ) levels are helpful
acetaminophen) can easily lead to acetaminophen
because frequently these patients are taking multiple
toxicity in the chronic pain patient. If acetaminophen
hepatically metabolized agents. Depending on the pa-
or NSAIDs are indicated, they can be added as sepa-
tient’s underlying medical conditions, follow-up labo-
rate agents to opioid-only medications in order to con-
ratory studies at 1^3 months and regularly thereafter
trol nonopioid dosage. An important opioid issue in
should be instituted. The patient can also be ques-
COP is that long-term analgesic use in migraine and
tioned as to dyspepsia, dark stool, or worsening of pre-
tension-type headache leads to a condition termed
existing asthma. Long-term medication use also in-
‘analgesic rebound headache,’ which is refractory to
creases the risk and consequences of adverse drug in-
normal therapy until analgesics are discontinued.11
If long-term opioids are used for chronic pain, a
a dysfunctional 5-HT or NE pain modulation pathway.
pain contract identifying the responsibilities of pa-
This may explain comorbid pain symptoms in patients
tients and prescribers is highly recommended and re-
with depression. Likewise, patients with chronic pain
quired in some states. Continued prescribing should
are more prone to depression due to the burden that
be tied to increased activity and productivity levels, as
daily, continuous pain can inflict. It is usually impossi-
well as other documentation of efficacy. The support
ble and unnecessary to separate these components.
of a pain psychologist to further evaluate mental
What is clear is that not all antidepressants have anal-
health and improvement in function is very desirable.
gesic characteristics and that the analgesic effect is in-
Laboratory testing to identify diversion and use of illic-
dependent of the antidepressant effect.1,13 Particularly
it substances should be considered at regular, un-
for TCAs, the dose for analgesia is well below thera-
scheduled intervals. Addiction is not thought to be a
peutic doses for depression, and the time to analgesic
frequent concern in the chronic pain population but
effect is much sooner than for antidepressant activity.
can occur.12 As the definition of addiction implies con-
It also appears that NE reuptake blockade, not just 5-
tinued use despite harm, and the chronic pain patient
HT reuptake blockade, is particularly important;
presumably derives a medical benefit from pain reduc-
hence, TCAs and SNRIs are the most widely used an-
tion, ‘addiction’ may need to be defined differently for
tidepressants for pain control. When TCAs are used,
this patient population or another term used. Certain-
secondary amines (nortriptyline, desipramine) are fre-
ly, dependence and tolerance can and do develop, but
quently preferred due to fewer adverse effects such as
many patients can maintain a stable opioid dose for
sedation, dry mouth, and orthostatic hypotension.
long periods of time. Others require changing to differ-
However, when sleep is poor and nocturnal bruxism
ent opioids periodically to maintain benefit. The most
is present, a tertiary amine (amitriptyline, imipramine)
common and disturbing adverse effect is constipa-
can be used at bedtime. TCAs are useful for most COP,
tion, which is managed initially whenever long-term
including musculoskeletal pains, neuropathic pains,
opioids are prescribed. Respiratory depression and or-
migraine, and tension-type headache. The newer
thostatic hypotension are rarely observed with careful
SNRIs, venlafaxine ( Effexor), duloxetine ( Cymbalta),
titration. Nausea, when it occurs, can usually be man-
and desvenlafaxine ( Pristiq), are used increasingly for
aged with a change in opioid without having to rely on
chronic pain, and particularly neuropathic pain. Cym-
adjunctive agents. Opioids are remarkably safe from a
balta and Pristiq are FDA-approved for certain neuro-
physiological standpoint when titrated appropriately.
pathic conditions.The selective serotonin reuptake inhib-
Regardless, the use of long-term opioid therapy
itors (SSRIs) such as paroxetine ( Paxil) and fluoxetine
should be reserved for dentists with special training
( Prozac), while as effective as other antidepressants for de-
or experience. Dentists are strongly encouraged to fol-
pression, do not possess analgesic properties.14 They cer-
low state medical board (physician) requirements for
tainly may be useful for treating depression in the COP
chronic opioid therapy, as this is becoming a highly
patient and hence improve coping and daily function,
scrutinized and regulated area of practice. For most
but actual pain levels may not decrease. The monoamine
dentists, patients requiring long-term opioid therapy
oxidase inhibitors (MAOIs) are no longer used for pain ex-
should be referred to qualified medical or dental prac-
cept possibly for refractory migraine. The other miscella-
titioners. For patients who are currently prescribed
neous antidepressants are less useful, although trazodone
opioids for chronic pain by another physician, dentists
can be used as a non ^ dependence-producing sleep ad-
should consult with or at least notify the opioid pre-
junct, and bupropion has less adverse sexual effects than
scriber regarding additional opioids that may be pre-
other antidepressants and has some support for neuro-
pathic pain.15 An important issue for dentistry is thatSSRIs and probably SNRIs can initiate bruxism in somepatients. The use of antidepressants for pain is complex,
and the limitations of this article do not allow an in-depthreview of indications, adverse effects, drug interactions,
Antidepressants have been used for chronic pain for
and other considerations in prescribing these agents.
some time (despite lack of FDA approval until recentlyfor some agents), and the link between depression andchronic pain is clear. It is known that descending pain
modulation pathways release serotonin (5-hydroxy-tryptamine or 5-HT ) and norepinephrine ( NE ) to sup-
The use of AEDs is common in pain practice, particu-
press pain transmission. The depressed patient has a
larly for neuropathic pain and the primary headaches.
dysfunctional 5-HT or NE system, which likely implies
These agents are thought to limit neuronal excitation
and enhance inhibition. Various sites of action include
voltage-gated ion channels (ie, sodium and calcium
channels), ligand-gated ion channels, the excitatory re-
ceptors for glutamate including N-methyl-D-aspartate
receptors, and the inhibitory receptors for GABA and
glycine. Carbamazepine ( Tegretol) was classically the
first line agent for typical trigeminal neuralgia (tic dou-loureux). Phenytoin has also been used but with lesssuccess. These drugs, however, have many adverse
effects and can induce serious blood dyscrasiasrequiring careful and regular laboratory monitoring.
As mentioned above, the CNS-acting muscle relaxants
Divalproexsodium ( Depakote) is frequently used for
(see Table) are generally not very useful for chronic
headache and neuropathic pain and is currently FDA-
muscular conditions and all are quite sedating. Impor-
tantly, cyclobenzaprine ( Flexeril) is structurally related
( Lamictal) is useful for neuropathic pain but life-
to the TCA amitriptyline, has similar effects, and can
threatening rash (epidermal necrolysis) makes this a
be useful for some pains and nocturnal bruxism. Addi-
second or third line agent. The introduction of gaba-
tionally, carisoprodol ( Soma), a derivative of mepro-
pentin ( Neurontin) to the USA in 1994 led to a resur-
bamate, has anxiolytic properties and the potential
gence in the use of AEDs for pain management.
for dependence. The antispastic agents baclofen ( Lior-
Although developed to mimic GABA, the agent has
esal) and tizanidine ( Zanaflex) are interesting medica-
no effect on GABA receptors but instead inhibits CNS
tions, however. Baclofen, a GABAB agonist, is useful
voltage dependent calcium channels and likely those
for some muscular complaints but is also effective for
involved in pain transmission. Later evidence suggest-
trigeminal neuralgia.18 Tizanidine, an alpha-2 agonist,
ed a role in increasing GABA synthesis, so the exact
has good muscle relaxing properties and like all alpha-
mechanism of action is unclear. What is clear is that
2 agonists has sedative and analgesic properties as
the medication was useful for a wide range of pain
conditions with minimal adverse effects except for se-dation and rare fluid retention.16,17 The agent is re-nally excreted unchanged and not significantly plasma
protein bound, making it very prescriber friendly. Newer AEDs were subsequently developed and have
The treatment of the primary headachesömigraine,
proven useful for chronic pain. These include tiaga-
tension-type headache, cluster headache, and their
bine ( Gabitril), topiramate ( Topamax), and pregabalin
variantsöis too complexa topic for this review. What
( Lyrica), which all have GABA-ergic and for some,
can be said is that pharmacologic therapy is divided
other pharmacodynamic effects such as inhibition of
into symptomatic treatments (opioid and nonopioid
calcium channels. Many of these agents are also used
analgesics and antiemetics where indicated), abortive
off-label by psychiatrists for anxiety and bipolar disor-
treatments for migraine and cluster headaches (‘ trip-
ders. Lyrica is the only drug FDA-approved for fibro-
tans,’ ergots, oxygen, steroids), and preventive agents
myalgia. The mechanism of levetiracetam ( Keppra),
(antidepressants, AEDs, beta blockers, lithium, verap-
another newer agent, is not known. Common to these
amil). The decision to proceed from symptomatic/
newer agents is the lack of serious adverse effects such
abortive therapy to preventive therapy is generally
as was seen with the older generation AEDs. Yet an-
based on the number of disability days per month due
other recently introduced drug, oxcarbazepine ( Trilep-
to headache. Although this varies among practitioners,
tal) functions similarly to carbamazepine as a sodium
approximately 6 disability days or more per month
channel blocker but without the significant incidence
usually leads to consideration of preventive therapy.
of serious blood dyscrasias. It does, however, have arelatively high incidence of hyperammonemia andsyndrome of inappropriate antidiuretic hormone hy-
persecretion ( SIADH ) which can also arise with otherAEDs with varying occurrence rates. As with the anti-
There are many more medications that can be dis-
depressants, the limitations of this article do not allow
cussed, including topical agents, but those drugs ad-
an in- depth review of indications, adverse effects, drug
interactions, and other considerations in prescribing
Important to the anesthesia provider or the dental sur-
geon is to distinguish why a patient may be using
these medications, as many are used ‘off-label,’ such
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seemingly small, altered sensations can be magnified.
We must understand that these perceptions are as real
8. van Tulder MW, Koes BW, Bouter LM. Conservative
to them as they seem unlikely to us as dentists. Added
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to this, patients with chronic pain are frequently, and
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understandably, distressed and also depressed. Those
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Blood dyscrasias are possible side effects of which
Which of the following side effects is most common
w hen opioi ds are prescr i be d conti n u o u sly forchronic pain ?
The risk for renal toxicity is enhanced when pro-
Which CNS neurotransmitter is thought to be most
longed use of NSAIDs is combined with which of
critical in mediating the analgesic effect of antide-
the following antihypertensive drug classes ?