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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 [email protected].
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 5. Arnold LM, Lu Y, Crofford LJ, et al. A double-blind, as the AEDs for psychiatric purposes or for pain man- multicenter trial comparing duloxetine with placebo in the agement. Patients with chronic pain can be a chal- treatment of fibromyalgia patients with or without major de- lenge for the general dentist as well as the dentist with pressive disorder. Arthritis Rheum. 2004;50:2974^2984.
sedation or general anesthesia training. These pa- 6. Becker DE. Pain management: part 1: managing acute and postoperative dental pain. Anesth Prog. 2010;57:67^79.
tients, in general, have dysmodulated pain control sys- 7. McQuay H, Carroll D, Jadad AR, Wiffen P, Moore A.
tems. They are frequently very somatically focused, so Anticonvulsant drugs for management of pain: a systematic 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 treatment of acute and chronic nonspecific low back pain: a to this, patients with chronic pain are frequently, and systematic review of randomized controlled trials of the most understandably, distressed and also depressed. Those common interventions. Spine. 1997;22:2128^2156.
with COP are all the more challenging since the surgi- 9. Rowbotham MC,Twilling L, Davies PS, Reisner L,Taylor cal interventions we provide, or for which we provide K, Mohr D. Oral opioid therapy for chronic peripheral and anesthesia, are in the area of pain reference. With central neuropathic pain. N Engl J Med. 2003;348:1223^ compassionate care, however, these people frequently 10. Dworkin RH, Backonja M, Rowbotham MC, et al. Ad- Pain is a part of the human experience and has ben- vances in neuropathic pain: diagnosis, mechanisms, andtreatment recommendations. Arch Neurol. 2003;60:1524^ efits as well as liabilities. In chronic pain, the liabilities usually outweigh the benefits. It is hoped that as ad- 11. Diener H-C, Limmroth V. Medication-overuse head- vances in pain pathophysiology and pharmacology ache: a worldwide problem. LancetNeurol. 2004;3:475^483.
are made, newer agents will be developed to reduce 12. Portenoy RK. Opioid therapy for chronic non-malig- the human suffering that chronic pain inflicts on indi- nant pain: a review of the critical issues. J Pain Symptom 13. MaxMB, Culnane M, Schafer SC, et al. Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood. Neurology. 1987;37:589^596.
14. Max MB, Lynch SA, Muir J, Shoaf SE, Smoller B, 1. McQuay HJ, Tramer M, Nye BA, Carroll D, Wiffen PJ, Dubner R. Effects of desipramine, amitriptyline, and fluoxe- Moore RA. A systematic review of antidepressants in neuro- tine on pain in diabetic neuropathy. N Engl J Med.
2. Collins SL, Moore RA, McQuay HJ, Wiffen P. Antide- 15. Semenchuk MR, Sherman S, Davis B. Double-blind, pressants and anticonvulsants for diabetic neuropathy and randomized trial of bupropion SR for the treatment of neuro- postherpetic neuralgia: a quantitative systematic review.
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16. Backonja M, Beydoun A, Edwards KR, et al. Gaba- 3. Wernicke J, Lu Y, D’Souza DN, Waninger A,Tran P. An- pentin for the symptomatic treatment of painful neuropathy tidepressants: duloxetine at doses of 60 mg QD and 60 mg in patients with diabetes mellitus: a randomized controlled BID is effective in treatment of diabetic neuropathic pain ( DNP ). In: Abstracts of the 2d Joint Scientific Meeting of the 17. Rowbotham M, Harden N, Stacey B, Bernstein P, American Pain Society and the Canadian Pain Society. May Magnus-Miller L. Gabapentin for the treatment of posther- 2004. J Pain. 2004;5(3 suppl 1):S48.
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4. Sindrup SH, Bach FW, Madsen C, Gram LF, Jensen TS. Venlafaxine versus imipramine in painful polyneuropa- 18. Sist T, Filadora V, Miner M, Lema M. Gabapentin thy: a randomized, controlled trial. Neurology. 2003;60: for idiopathic trigeminal neuralgia: report of two cases. Neur- 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 ?

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