Pharmacology in Orofacial Pain Robert W Mier DDS, MS Tufts University School of Dental Medicine.

Pharmacology in Orofacial Pain

Robert W Mier DDS, MS Tufts University School of Dental Medicine

Categories of Medications Used

• Opioid

• Non-opioid

• NSAID

• Antidepressants

• Anticonvulsants

• Muscle relaxants

• Hypnotics/Anxiolytics

• Topicals

• Injectables

Available Resources

• Lexicomp

• Epocrates

• PDR

• Textbooks

• Published research

Recent Text Specific to Orofacial Pain

"Doctors give drugs of which they know little, into bodies, of which they know less, for diseases of which they know nothing at all." -Voltaire

"Of several remedies, the physician should choose the least sensational." -Hippocrates

"All drugs are poisons the benefit depends on the dosage.”-Philippus Theophrastrus Bombast

"If we doctors threw all our medicines into the sea, it would be that much better for our patients and that much worse for the fishes." -Supreme Court Justice Oliver Wendel Holmes, MD

Nothing happens until an axon depolarizes….

Pain Pathways

Perception: opioids, α2-agonists, TCAs,SSRIs, SNRIs

Trauma

Peripheral nociceptors

Spinothalamictract

Ascending input Descending modulation

Dorsalhorn

Dorsal root ganglion

Peripheralnerve

Pain

Transmission: LAs,opioids, α2-agonists

Transmission: LAs, opioids

Transduction: LAs, capsaicin,anticonvulsants, NSAIDs, ASA, acetaminophen, nitrate

Modulation: TCAs,SSRIs, SNRIs

TCAs=tricyclic antidepressants; SSRIs=selective serotonin reuptake inhibitors; SNRIs=serotonin-norepinephrine reuptake inhibitors; LAs=local anesthetics; NSAIDs=nonsteroidal anti-inflammatory drugs; ASA=aspirin.

Adapted with permission from Kehlet H, Dahl JB. Anesth Analg. 1993;77:1048-1056.

Pharmacologic Targets: A Mechanistic Approach

Nociceptive vs Neuropathic Pain

1. International Association for the Study of Pain. IASP pain terminology. Available at: http://www.iasp-pain.org/terms-p.html#Neuropathic%20pain. Accessed March 9, 2006. 2. Portenoy RK, Kanner RM, eds. Pain Management: Theory and Practice. Philadelphia, Pa: FA Davis Co; 1996;248-276. 3. NPC/JCAHO. Pain: Current Understanding of Assessment, Management, and Treatments. December 2001.

Nociceptive1,2

• Caused by activity in neural pathways in response to stimuli potentially damaging to tissue

• Responsive to analgesics

Neuropathic1,3

• Initiated or caused by primary lesion or dysfunction in the nervous system

• Responsive to neuromodulators

• May require poly-pharmacotherapy

Mixed• Caused by both

primary injury and secondary effects

• May require poly-pharmacotherapy

Polypharmacy

Polypharmacy

Treat two pathophysiolgically

distinct but comorbid conditions

Treat adverse

effects of primary drug

Boost or augment the

efficacy of the primary

treatment

Provide acute amelioration while

awaiting the delayed effect of

another medication

Treat intervening

phases of an illness

Preskorn SH. J Pract Psychiatr Behav Health. 1995;1:92-98

Evaluation of Research

• Most studies on chronic pain do not address orofacial pain. Typically back pain, fibromyalgia, and neuropathic pain (diabetic neuropathy and post-herpetic neuralgia). Extrapolation of results to the application on orofacial pain.

• Two important concepts to take into account when evaluating research on pharmacological agents:• NNT: Number Needed to Treat

• The number of patients that need to be treated for one to benefit compared with a control in a trial.

• The lower the number the better

• NNH: Number Needed to Harm

• The number of patients that need to be exposed for one to experience harm (side effect)

• The higher the number the better

Efficacy of medication for orofacial pain

The 60 most common medications are listed, but it is clear that the evidentiary basis for using them to treat orofacial pain is limited.

The number of studies for each medication listed is split into how often it appears in the literature for each heading.

In addition to a very low number of existing studies on medications used specifically for orofacial pain, among those that do exist many are methodologically flawed and the populations studied were heterogenous. Thus we have to extrapolate from studies in other fields and patient populations.

Clark GT, Dionne RA. Orofacial Pain: A Guide to Medications and Management. Wiley-Blackwell. 2012

60 Most Common Orofacial Pain Medications

Clark GT, Dionne RA. Orofacial Pain: A Guide to Medications and Management. Wiley-Blackwell. 2012.

Efficacy of medication for orofacial pain

Another factor that may affect the evaluation of treatment outcome in response to drug therapy is the fluctuating nature of orofacial pain.

The concurrent presence of psychological problems in the patient population treated may also influence the response.

Therefore the pharmacologic management of orofacial pain must rely on the same principles that apply to all drug therapy: demonstrated efficacy for the indication, an acceptable side-effect liability, and safety when given for prolonged periods.

Clark GT, Dionne RA. Orofacial Pain: A Guide to Medications and Management. Wiley-Blackwell. 2012

30 Most Common Orofacial Pain Diseases

• Primary and Secondary Myalgia

• Myofascial Pain

• Chronic Widespread Pain and Fibromyalgia

• TMJ DDR

• TMJ DDwR

• TMJ Arthritis• TMJ Localized Arthritis

• Polyjoint osteoarthritis and TMJ

• Rheumatic arthritis and TMJ

• Temporal Arteritis

• Idiopathic trigeminal sensory neuropathy


• Migraine

• Cluster Headache and autonomic cephalalgias

• Tension-Type Headache

• Chronic Daily Headache

• Facial pain related to trigeminal neuritis

• Facial pain related to trigeminal neuroma

• Facial pain related to trigeminal neuralgia

• Facial pain related to a chronic trigeminal neuropathy

• Facial pain related to postherpetic neuralgia

• Burning mouth symptoms


• Pemphigus vulgaris

• Benign mucous membrane pemphigoid

• Lichen planus

• Mucositis

• Other chronic ulcerative conditions of the mouth

• Cancer pain of the jaw

• Dyskinesia

• Dystonia

• Bruxism

• Habitual parafunction and spontaneous/secondary hypertonicity

Choosing a Medication for Pain Management

Summarized from WHO acute pain management guidelines

Pain Rating (scale 0-10) Primary Medications Adjunct Medications

Mild pain or a rating of 0-3 Nonopioid such as an NSAID or acetaminophen

Antidepressant or anticonvulsant

Moderate pain or a rating of 4-6

Weak opioid, such as codeine or hydrocodone

NSAID, acetaminophen, COX-2 inhibitors, antidepressant, or anticonvulsant

Severe pain or a rating of 7-10

Strong opioid, such as morphine, oxycodone, or fentanyl

NSAID, acetaminophen, antidepressant, or anticonvulsant

Opioids

• Important and effective medications for both acute and chronic pain.

• Opioids have no ceiling maximum doses.

• Action both on directly inhibiting neurons as well as activation of the descending inhibitory pathways.

• Due to side effects and abuse potential, a risk/benefit analysis should accompany any decision to prescribe this class that encompasses existing medications, medical and psychological status, and the pain level.

• Mild/moderate pain typically warrants Schedule III opioids which include Codeine and Hydrocone. • These are normally provided as combination medications with either NSAID

or Acetaminophen. This then requires attention if it is to be for long-term use in order to avoid the complications with the combination agent. In addition codeine use deserves caution with SSRI use due to liver metabolic pathways.

• Also not recommended for chronic use due to higher prevalence of nauseau than many other opioids, and due to a high prevalence of polymorphisms in the population that interferes with metabolism.

Opioids

• Severe pain typically warrants Schedule II opioids which include morphine, oxycodone, fentanyl, hydromorphone, oxymorphone, and methadone.

• Two primary issues with side effects: drug-drug interactions leading to increased CNS depressant effects, and genetic variations that contribute to adverse effects.

• Most common side effects are constipation, nausea, vomiting, pruritis, myoclonus, dry mouth, respiratory depression (particularly with drug interactions), somnolence, sedation, and hypogonadism. Dependence and tolerance are issues of concern as well, particularly in the face of significant inter-patient variability.

• Appropriate use in chronic pain that has been unresponsive to alternate methods for non-cancer pain.• Passik SD. Monitoring outcomes during long-term opioid therapy for

noncancer pain: results with the Pain Assessment and Documentation Tool. J Opioid Manage 2005 Nov-Dec; 1(5): 257-266.

Opioids

• Chou R. Clinical Guidelines for the Use of Chronic Opioid Therapy in Chronic Noncancer Pain. Pain. 2009 February; 10(2): 113-130.

• Set consensus guidelines for American Pain Society and American Academy of Pain Medicine.

• Chronic opioid therapy (COT) can be an effective therapy for carefully selected and monitored patients with chronic noncancer pain.

• However, also associated with potentially serious issues, including adverse effects and outcomes related to abuse potential.

• Need to be cognizant of the concepts of patient selection, risk stratification, informed consent, opioid management plans, initiation and titration of therapy, concept of rotation, monitoring, and indications for discontinuation of therapy.

• Risk stratification pertaining to outcomes with the misuse, abuse, addiction, and diversion of opioids is an important but relatively undeveloped skill in providers.

• The factor that appears to be most strongly predictive of abuse is personal or family history of alcohol or drug abuse.

• Evidence on methods to accurately assess the potential benefits of COT is limited, however RCTs demonstrate that it is most applicable to patients with moderate-severe pain who have not responded to nonopioid therapies.

Opioids

• Chou R. Clinical Guidelines for the Use of Chronic Opioid Therapy in Chronic Noncancer Pain. Pain. 2009 February; 10(2): 113-130.• Initial treatment with opioids should be regarded as a therapeutic trial to

determine if COT is an appropriate therapy.

• Consideration to a benefit-risk assessment for each patient is crucial, and consideration to the goals, expectations, and possible alternatives should be considered.

• Initial dosing and opioid selection should be individualized according to the health status, previous opioid exposure, attainment of therapeutic goals, and predicted or observed harm to the patient.

• There is insufficient evidence to recommend short-acting over long-action opioids, or as-needed versus around-the-clock dosing.

• Initial dosing in opioid-naïve patients or those with modest exposure should be to start low and titrate slowly to minimize adverse effects.

• Opioid rotation is a potential strategy for patients who have intolerable side effects or inadequate benefit. The theory is based on concepts of incomplete cross-tolerance to the analgesic and non-analgesic effects and the high degree of individual variation in patient response.

• Research gaps exist in methods of providing informed consent, components of opioid management plans, balancing risk/benefit of COT, rotation, and the treatment of breakthrough pain.

Opioid Terms

• Abuse: Any use of an illegal drug, or the intentional self-administration of a medication for a nonmedical purpose such as altering one’s state of consciousness.

• Addiction: A primary, chronic, neurobiologic disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving.

• Physical dependence: A state of adaptation manifested by a drug class-specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.

• Tolerance: A state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more opioid effects over time.

Opioids

• Noble M. Long-term opioid management for chronic noncancer pain. Cochran Collaboration Review. Cochrane Library 2010; Issue 1: 1-70.• Many patients discontinue long-term opioid therapy due to adverse

events or insufficient pain reduction; however, evidence suggests those who are able to continue on therapy experience clinically significant pain relief.

• Rate of observed signs of opioid addiction in the studies included in the review were extremely low, at 0.27%. This is particularly true in studies that prescreened chronic pain patients for consideration of COT.

• Szumita RP. Understanding and Managing Patients with Chronic Pain. Oral Maxillofacial Surg Clin N Am. 2010; 22: 481-494.• Stressed appropriate diagnosis to justify opioid therapy consideration.

• Recommended that psychologists play a major and unique role in assessing and managing patients on COT. Both before onset of treatment and during therapy.

Opioids

• Kalso E. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. Pain. 2004; 112: 372-380.• 15 studies up to 2003 of RCT placebo-controlled studies

demonstrated a mean decrease in pain intensity of at least 30%, and was comparable in neuropathic and musculoskeletal pain. 80% of the patients experienced at least one adverse event.

• No apparent predictive factors for opioid sensitivity, implied that each patient needs to be individually trialed.

• Turk DC. Treatment of chronic non-cancer pain. Lancet. 2011; 377: 2226-36.• Stressed that opioids are rarely a first-line treatment, and should be

considered a second or third-line treatment in chronic noncancer pain patients.

• Discussed issues surrounding misuse and diversion of opioids, suggesting that as many as 45% of patients taking opioids for noncancer pain are engaging in aberrant drug-taking behaviors.

Opioids

• Passik SD. Monitoring outcomes during long-term opioid therapy for noncancer pain: results with the Pain Assessment and Documentation Tool. J Opioid Manage 2005 Nov-Dec; 1(5): 257-266.

• This study demonstrated in general, patients who are in pain and are being medically managed with opioids are receiving treatment for a specific reason and do not become dependent, and had QoL improvements that were modest but meaningful.

• Akbik H. Validation and clinical application of the Screener and Opioid Assessment for Patients with Pain (SOAPP). J Pain Symptom Manage. 2006 Sep; 32(3): 287-293. • Identified 5 factors for high risk of abuse behavior: History of substance abuse,

legal problems, craving medication, heavy smoking, mood swings.

• Strasser F. Update on adjuvant medications for chronic nonmalignant pain. Pain Pract. 2003 Dec; 3(4): 282-297. • Proposed guidelines that support the chronic use of opioids for chronic

nonmalignant pain.

• The opioids are converted in large part to polar metabolites (mostly glucuronides), which are then readily excreted by the kidneys.

• Codeine, oxycodone, and hydrocodone undergo metabolism in the liver by P450 isozyme CYP-2D6.

• Genetic polymorphism of CYP-2D6 has been documented and linked to the variation in analgesic response seen among patients.

• In the case of codeine, conversion to morphine may be of greater importance because codeine itself has relatively low affinity for opioid receptors.

Opioid Metabolism

Common Side Effects

51 % of all patients taking oral opioids experience at least 1 adverse event

22% discontinue therapy due to AE

25 % dry mouth

21 % nausea

15 % constipation

14 % dizziness

13 % pruritis

10 % vomiting

Moore RA, McQuay HJ: Prevelance of opioid adverse events in chronic non-malignant pain: Systematic review of randomoized trials of oral opioids. Arth Research and Therapy, 2005.

Management of Opioid Side Effects

McNicol E et al. J Pain. 2003;4:231-256.

Side Effects AmeliorationConstipation Treat prophylactically with stool

softeners, bowel stimulants; nonpharmacologic measures; switch opioids; peripherally acting opioid antagonists (alvimopan, methylnaltrexone)

Nausea and vomiting

Switch opioids; antiemetics

Sedation Lower doses (if possible); add coanalgesics; add stimulants; switch opioids

Itching Switch opioids; add antihistamines

Endocrine dysfunction/reduced libido

Switch opioids; endocrine monitoring; testosterone replacement; endocrine consultation

Edema and sweating

Switch opioids

Dizziness Antivertiginous agents (eg, scopolamine)

Confusion Titrate dose; switch opioids

• Codeine

• Dihydrocodeine

• Hydrocodone

• Oxycodone

OPIOID ANALGESICS

Recommended

• Morphine

• Oxymorphone

• Hydromorphone

• Levorphanol

• Methadone

• Fentanyl

• *Tramadol (Ultram)• *Tapentadol (Nucynta)

Opioid Equivalency Table

• Propoxyphene (Darvon)

• Pentazocine (Talwin)

• Meperidine (Demerol)

• Partial agonists (Buprenorphine)

• Agonist-antagonists (Butorphanol)

OPIOID ANALGESICS

Not Recommended

• OT – a process of negative cellular adaptation that leads to diminished effects of opioids

• Accompanied by the activation of a pro-nociceptive system, a positive cellular adaptation

• Activation of NMDA-R and protein kinase C, as well as regulation of glutamate transporters has been implicated in the mechanisms of OT

• Neuroplasticity associated with the development of OT may activate the pro-nociceptive mechanism in the CNS that could counteract the analgesic effect of opioids and lead to OIH

Ballantyne and Mao: NEJM, 2003; Mao et al: J Neurosci, 1994; Mao et al: Pain, 1995

Opioid Tolerance and Opioid Induced Hyperalgesia

Non-opioid analgesics

• Acetaminophen

• Rapid onset and short half-life

• Typical dosing at 4-6h increments

• 4000mg ceiling to not be exceeded, FDA recommends 3200mg

• Liver toxicity is primary adverse effect, due to a toxic metabolite produced by CYP450 pathway.

• Excellent for acute pain management, including acute flare-up of a chronic condition.

• Useful when combined with adjuvant analgesics

• Could be first-line in treating the chronic conditions of:

• Osteoarthritis: Conflicting results of studies compared to NSAIDs

• Chronic Musculoskeletal Pain: Useful in elderly over NSAIDs

• Episodic Headache: Risk of MOH

• Towheed TE. Acetaminophen for osteoarthritis. Cochrane Database Syst Rev 2006 Jan.1:CD004257.


• Salicylates (ASA and Diflunisal)• ASA carries side effect risks for gastric irritation and ulceration

• Limits use for chronic conditions

• Inhibits prostaglandin synthesis

• Due to effects on platelet function, avoid in liver disease, bleeding issues and patients on anticoagulants.

• Typical dosing at 500-1000mg q4-6h, maximum 4000mg/day

• Diflunisal (Dolobid) is more effective as an analgesic than ASA

• Diflunisal has fewer side effects

• Similar concerns bleeding

• Typical dosing at 1000mg to start, and 500mg BID

NSAIDs

• One of most well-studied drug classes for acute inflammatory pain

• Consideration for chronic use affected by gastric and kidney concerns

• Mixed results in chronic orofacial pain, particularly in myogenous pain

• Non-selective Cox Inhibitors and Selective Cox-2 Inhibitors

NSAIDs

• Non-selective Cox Inhibitors:

• Ibuprofen: 200-800mg, typical maximum dose at 2400mg/day, but 3200mg/day has been used in osteoarthritis patients• Side effects: Edema, HA, dizziness, drowsiness, tinnitus, rash, GI

disturbances, bleeding issues, and nausea are common in this class of drugs as a whole.

• Singer E. A controlled evaluation of ibuprofen and diazepam for chronic orofacial muscle pain. J Orofac Pain 1997 Spring; 11(2): 139-146.

• Thie NM. Evaluation of glucosamine sulfate compared to ibuprofen for the treatment of temporomandibular joint osteoarthritis: a randomized double blind controlled 3 month clinical trial. J Rheumatol 2001; 28: 1347-1355.

• Very poor data for use in chronic pain aside from RA

• Naproxen: 500-550mg to start, then 250-275 q6-8h. OTC forms at 220mg BID• Long half-life, thus prevents increased dosing without complication

potential

• Ta LE, Dionne RA. Treatment of painful TMJs with a Cox-2 inhibitor: a randomized placebo-controlled comparison of celecoxib to naproxen. Pain 2004. Sep; 111(1-2): 13-21. Reported Naproxen had a significant effect on outcomes reducing pain compared to placebo as well as celecoxib.

NSAIDs

• Ketoprofen (Orudis): 50mg q6-8h, maximum 300mg/day

• Meclofenamate Sodium: 50-100mg q6-8h, maximum 400mg/day

• Piroxicam (Feldene): 10-20mg/day, long half-life so once/day dosing

• Diclofenac (Voltaren): 50mg BID/TID, maximum 150mg (Flector patch also)• Diclofenac potassium sachet (Cambia): acute migraine abortive. Lipton RB.

Efficacy and tolerability of a new powdered formulation of diclofenac potassium for oral solution for the acute treatment of migraine: Results from the International Migraine Pain Assessment Clinical Trial (IMPACT). Cephalalgia 2010 Nov; 30(11): 1336-1345.

• Ekberg EC. Diclofenac sodium as an alternative treatment of TMJ pain. Acta Odont Scand 1996. June; 54(3): 154-159

• Kubitzek F. Analgesic efficacy of low-dose diclofenac versus paracetamol and placebo in postoperative dental pain. J Orofac Pain 2003; 17(3): 237-244.

• Nabumetone (Relafen): 1000-2000mg/day (divided BID if desired), maximum 2000mg/day, keep duration as short as possible. Longer half-life, slower onset, well-tolerated.• Non-selective, but does not inhibit the gastroprotective prostaglandin, so better

tolerated and fewer gastric concerns.

NSAIDs

• Selective Cox-2 Inhibitors:

• Based on the hypothesis that Cox-1 is constitutively distributed throughout the body, while Cox-2 is limited to specialized tissues and is induced during inflammation, thus the Cox-2 inhibitors should have therapeutic effects devoid of the typical NSAID toxicity.

• Discovered that a myocardial risk exists. This has since been expanded to all NSAIDs. Thus care should be exercised when using in patients with cardiac histories.

• Celecoxib (Celebrex): 100-200mg BID. Recommended for osteoarthritis, no data on myogenous pain. Use in orofacial pain studied in Ta and Dionne.

• Meloxicam (Mobic): 7.5-15mg qd. Slow onset and may take time for benefit to be realized.

• Etodolac (Lodine): 200-400mg q6-8h. Maximum 1000mg/day. Long-term use the maximum is 600mg/day. 10-fold selectivity for Cox-2.


• Tramadol (Ultram)• Value in chronic conditions more than acute

• Categorized as a non-scheduled substance

• Binds to mu-opioid receptor

• Serotonin and NE reuptake inhibition (similar to TCAs)

• Recent evidence suggests withdrawal, abuse and dependence potential

• Typical starting dose at 25-50mg/day, increasing 25-50q 3 days

• Maximum dose at 400mg/day

• Target for QID dosing for symptom relief

• Can be combined effectively with Acetaminophen

• Side effects: nauseau, dizziness, dry mouth, constipation, drowsiness

• Tapentadol (Nucynta)• Similar in action to Tramadol, with increased potency.

• Typical dosing at 50-100mg q4-6h prn.

• Equal effectiveness as oxycodone or morphine with a lower incidence of GI adverse effects.

• No active metabolites, unlike Tramadol, thus expected to be less effected by polymorphic differences in individuals.• Nossaman VE. Advances in Perioperative Pain Management: Use of Medications with Dual Analgesic

Mechanisms, Tramadol and Tapentadol. Anesth Clinics 2010 Decemeber; 28(4): 647-666.

Systemic Corticosteroids

• Methylprednisolone and Prednisone typically used for oral dosing.• Suppression of inflammation while desirable, can lead to potentially

critical side effects. These patients must be monitored and if long-term use is necessary must be tailored to the lowest possible dose to achieve effect. Use for longer than one week requires tapering for withdrawal.

• Usual dosing is similar to a Medrol Dosepack: 4mg Methylprednisolone with a descending dose beginning with 6 pills on Day 1 and decreasing by one pill/day until gone.

• Best to limit to episodic intervention, and avoided in presence of any infective process.

• Corticosteroid use has analgesic properties as well, likely stemming from blocking C-fiber transmission.

• TMJ direct injections have validity, but judicious use should be followed in cases that prove to be recalcitrant to all other treatments, with limited potential for negative effects.

• Moystad A. Injection of sodium hyaluronate compared to a corticosteroid in the treatment of patients with temporomandibular joint osteoarthritis: a CT evaluation. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008. Feb; 105(2): 53-60.

Systemic Corticosteroids

Choosing an Analgesic Agent

• Adjuvant analgesic: any drug with a primary indication other than pain, but with analgesic properties in some painful conditions.

• Usually administered with traditional analgesics, but could be used alone. Co-administration is to enhance pain relief, address pain that has not or has insufficiently responded, and allow reduction of the opioid dose to reduce adverse effects.

• Main classes are TCAs, SSRI, SNRI, and Anticonvulsants.

• Very few comparative trials exist, so proper selection is largely a trial and error process. Sequential single-drug trials are highly recommended before moving on to the next agent.

• Goals are not necessarily to eliminate pain completely, but to achieve appropriate endpoints for each patient. Primarily the prevention and reduction of pain, improvement in function, improvement in mood and sleep patterns, and anticipation and treatment of side effects.

Anticonvulsants/Antiepileptics

• When you begin to consider the use of these agents in treatment, the presumptive diagnosis should be neuropathic in origin. To include neuralgias, neuritis, neuromas, and neuropathies.

• The twelve most common agents in this category are:• Carbamazepine, oxcarbazepine, lamotrigine, levetiracetam,

zonisamide, phenytoin, gabapentin, pregabalin, baclofen, valproic acid, topiramate, and lidocaine.

• Carbamazepine is approved for use in TN, but the others are off-label for suppression of neuropathic pain.

• Side effects are significant due to systemic suppression effects, thus use requires titration upward to balance the untoward side effects with pain relief.

• 2008 FDA advisory for suicidal behavior and ideation

Anticonvulsants/Antiepileptics• Carbamazepine (Tegretol): 200mg BID, titrated to effective range of 600-1200mg/day

• Action on voltage-gated sodium channels by stabilizing the inactivated state

• Metabolized by CYP450 pathway, and is self-inducing so initial dose will become less effective over time.

• Thus periodic serologic assessment is necessary on liver function and drug level

• Side effects: Rash, drowsiness, diplopia, and balance issues. 2007 FDA warning on potential for Stevens-Johnson syndrome. Potential for aplastic anemia, leukopenia and thrombocytopenia.

• Jorns TP. Evidence-based approach to the medical management of trigeminal neuralgia. Br J Neurosurg 2007 Jun; 21(3):253-261. Review demonstrated Carbamazepine is first-line treatment for TN.

• Efficacy in other neuropathic conditions is sparse, suggesting it is not a first-line treatment primarily due to the potential for significant side effects. Used in lower doses usually <400mg BID. Second-line treatment if gabapentin is ineffective.

• Oxcarbazepine (Trileptal): 300mg BID, titrated up 300mg/day every 3 days to a maximum of 1800-2400mg/day

• Structurally similar to carbamazepine with similar therapeutic properties while potentially avoiding many of the toxicities of concern.

• Action on voltage-gated sodium channels and modulation of voltage-activated calcium channels.

• Not FDA approved for TN, but is used off-label for this purpose.

• Considered a prodrug, in that it is a nonactive drug when ingested and its metabolite is the active compound.

• Weak inducer of the CYP pathway, thus the effective dose remains more stable.

• Side effects: Hyponatremia (should be followed during maintenance), rash, minimal drug-drug interactions.

• Limited data on use in other neuropathic conditions, but may have potential.

• Nasreddine W. Oxcarbazepine in neuropathic pain. Expert Opin Investig Drugs. 2007 Oct; 16(10): 1615-1625.


• Lamotrigine (Lamictal): 100-400mg/day range of effectiveness, as 25-50mg TID typical. Increasing doseage slowly every 5-7 days to avoid side effects.

• Action by stabilizing inactivated sodium channels, and possibly suppressing the neuronal release of glutamate.

• Side effects: Somnolence, dizziness, ataxia, rash, and insomnia. Slower titration can be an issue in patient with severe pain at presentation.

• General lack of published studies on efficacy in TN and other neuropathic disorders.

• Silver M. Double-blind, placebo-controlled trial of lamotrigine in combination with other medications for neuropathic pain. J Pain Symptom Manage. 2007 Oct;34(4):446-454. Lamotrigine had no effect on neuropathic pain conditions alone or in combination with other agents.

• Gabapentin (Neurontin): 100mg TID, with gradual increase of 300mg/day every 3-4 days for a target of 1800mg. Maximum dose is 3600mg.• Appears to work on voltage-dependent calcium channels.

• Has analgesic properties as well, is well-tolerated and has few drug-drug interactions.

• Excreted unchanged in the urine, so caution in patients with renal impairment.

• Side effects: Peripheral edema, somnolence, dizziness, drowsiness, nauseau, fatigue. These are typically self-limiting and can be managed with slow titration.

• Not first line for TN, but has been tested with success in other neuropathic conditions.

• Mellegers MA. Gabapentin for neuropathic pain: systematic review of controlled and uncontrolled literature. Clin J Pain. 2001 Dec; 17)4): 284-295.


• Pregabalin (Lyrica): 300-600mg/day BID/TID. Initial dosing at 150mg/day beginning HS.

• GABA analog that has analgesic, anticonvulsant, and anxiolytic properties.

• Effects on calcium channels, and inhibiting release of neurotransmitters including glutamate, NE, and substance P.

• Side effects: Dizziness, somnolence (which decreases), weight gain, peripheral edema, and is excreted unchanged in the urine. Typically well-tolerated.

• No evidence for efficacy in TN, but has shown good outcome in other neuropathic conditions.

• Tzellos TG. Efficacy of pregabalin and gabapentin for neuropathic pain in spinal-cord injury: an evidence-based evaluation of the literature. Eur J Clin Pharmacol. 2008 Sep; 64(9):851-858.

• Baclofen (Lioresal): 5-10mg HS to start, increasing by 5mg each week and titrated up to 50-75mg total delivered equally TID.

• GABA-B agonist, inhibits calcium influx into presynaptic terminals in spinal cord. Inhibits neuronal activity at the spinal level, and depresses the CNS.

• Due to these effects, there is GABA desensitization and tolerance to an agonist thus the initial dose will likely need to be increased.

• Side effects: Drowsiness, confusion, dizziness, and weakness. Abrupt withdrawal should be avoided due to possible seizure and hallucination.

• Used in TN, but also classified as an anti-spasmodic and used for musculoskeletal pain as well.

• Sparse publication on efficacy in TN and neuropathic pain. Only tested in intrathecal spinal delivery.

• Off-label use typically as an adjuvant in polypharmacy approach.

• Fromm GH. Baclofen as an adjuvant analgesic. J Pain Symptom Manage. 1994: 9: 500-509.


• Zonisamide (Zonegran): Initial dose of 100mg/day, titrated every 2 weeks to a maximum of 600mg/day.

• Metabolized by liver, leading to pharmokinetic variability. Exact mechanism of action is unknown but may involve GABA and sodium channels.

• Generally well-tolerated

• No literature in TN efficacy. Evidence of benefit in other neuropathic conditions.

• Kothare SV. Zonisamide: review of pharmacology, clinical efficacy, tolerability, and safety. Expert Opin Drug Metab Toxicol. 2008 Apr; 4(4): 493-506.

• Topiramate (Topamax): Initial dosing at 25mg BID, increasing 50mg/week to effective range of 200-400mg/day.

• Potentiates GABA responses and increases GABA levels in CNS, also blocking the AMPA excitatory receptor and a weak carbonic anhydrase inhibitor.

• Primarily used for chronic HA.

• Not been suggested for use in TN, and has not demonstrated efficacy in neuropathic pain conditions.

• Approved as a preventative agent in migraine, and potential in Cluster HA.

• Gingival inflammation potential dental side effect

• * Sharav Y. The analgesic effect of amitriptyline on chronic facial pain. Pain. 1987 Nov: 31(2): 199-209. TCAs must also be considered in treating neuropathic pain either as a single treatment or in combination with the agents mentioned above.


Dworkin RH. Recommendations for the Pharmacological Management of Neuropathic Pain: An Overview and Literature Update. Mayo Clin Proc 2010 March; 85(3)(Suppl): S3-S14.

Muscle Relaxants

• Skeletal muscle relaxants and Antispasticity drugs

• Caution for using drugs in this category due to significant potential for side effects (particularly sedation and weakness) and drug-drug interactions, particularly in the elderly.

• Also the potential for development of dependence

• Little data available on the efficacy in orofacial pain

• Spasticity is defined as an upper motor neuron disorder, and the drugs used to treat this typically carry a higher risk of significant side effects.

• Skeletal muscle relaxants are considered effective against lower motor neuron concerns, which can present as painful musculoskeletal conditions.

Muscle Relaxants

• These agents also possess analgesia equivalent to acetaminophen and ASA.• Manfredini D. Muscle relaxants in the treatment of myofascial face pain.

A literature review. Minerva Stomatol. 2004 Jun; 53(6): 305-313.

• See S. Skeletal muscle relaxants. Pharmacotherapy. 2008 Feb; 28(2): 207-213.

• Antispastics: Baclofen, tizanidine, dantrolene, tiagabine, and benzodiazepines.

• Skeletal muscle relaxants: Cyclobenzaprine, methocarbamol, metaxalone, ophendrine, chlorzoxazone, and carisoprodol.

• Chou R. Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions: a systematic review. J Pain Symptom Manage. 2004 Aug; 28(2): 140-175.• Concluded that cyclobenzaprine, carisoprodol, orphenadrine, and

tizanidine are effective compared to placebo. Metaxalone, methocarbamol, chlorzoxazone, baclofen, and dantrolene had no supporting evidence.

Muscle Relaxants

• Carisoprodol (Soma): 350mg QID• Thought to activate GABA-A receptors in descending reticular formation and spinal cord.

• A prodrug, metabolized to meprobamate

• Side effects: Psychological and physical dependence issues, drowsiness, drug interaction potential particularly respiratory depression.

• Cyclobenzaprine (Flexeril): 5-10mg HS, increasing 10mg every 3-7 days and evolve to TID.• FDA approved in use with acute painful musculoskeletal conditions.

• Chemical structure similar to TCAs, with strong anticholinergic effects and long half-life.

• Assumed to function at the level of the brainstem rather than the spinal cord, and antagonizes serotonin receptors.

• Side effects: Anticholinergic (drowsiness, urinary retention, dry mouth), avoid with cardio hx.

• Effectiveness in orofacial pain and other musculskeletal conditions has been studied:

• Herman CR. The effectiveness of adding pharmacologic treatment with clonazepam or cyclobenzaprine to patient education and self-care for the treatment of jaw pain upon awakening. J Orofac Pain. 2002; 16(1): 64-70.

• Borenstein DG. Efficacy of a low-dose regimen of cyclobenzaprine hydrochloride in acute skeletal muscle spasm: results of two placebo-controlled trials. Clin Ther. 2003; 25: 1056-1073.

Muscle Relaxants

• Metaxalone (Skelaxin): 800mg TID/QID• Unknown mechanism, but assumed to be general depression of the CNS.

• Advantages are reduced sedation, diminished abuse potential, and short half-life.

• Side effects: Drowsiness, dizziness, headache, and irritability. Avoided in patients with a history of renal or hepatic failure or blood dyscrasias.

• Chlorzoxazone (Lorzone): 250-750mg TID• Action primarily in spinal cord and subcortical regions of the brain via

inhibition of multisynaptic reflex arcs. No direct action on contractile mechanism.

• Side effects: Dizziness, drowsiness, GI irritation. Risk for respiratory depression when combined with other drugs.

• Methocarbamol (Robaxin): Initial dosing at 1500mg QID for 2-3 days, then 750mg QID• Action is central and does not directly relax skeletal muscles.

• Side effects: Discolored urine and impaired mental status.

Muscle Relaxants

• Orphenadrine (Norflex): Typical dosing is 100mg BID/TID• Assumed to be a non-competitive antagonist of NMDA receptors and

histamine receptor antagonist. Similar structure and action as antihistamines.

• Side effects: Typical anticholinergic side effects

Antispastic Drugs:

• Baclofen (Lioresal): Discussed previously as an anticonvulsant.

• Tiagabine (Gabatril): 4mg/day for 1 week, the increase by 1 tablet/day per week. • Action is by selective inhibition of GABA transport.

• Side effects: Dizziness, weakness, and shakiness.

• FDA approved as an adjunctive anticonvulsant.

• Novak V. Treatment of painful sensory neuropathy with tiagabine: a pilot study. Clin Auton Res. 2001 Dec; 11(6): 357-361.

• Use in orofacial pain has been studied, and it’s use has been suggested for use in bruxism reduction and TMD: • Kast RE. Tiagabine may reduce bruxism and associated temporomandibular joint

pain. Anesth Prog. 2005; 52(3): 102-104.

Muscle Relaxants

• Tizanidine (Zanaflex): Initial dose at 4mg divided TID, up to 12mg divided TID• Action is as a central alpha(2) adenoreceptor agonist exerting its effect presynaptically

on the motor neuron similar to clonidine.

• Quick onset and short half-life. Liver effects, which require monitoring.

• Side effects: Drowsiness, hypotension, dry mouth, bradycardia, and dizziness.

• Kirmeier R. Evaluation of a muscle relaxant on sequelae of third molar surgery: a pilot study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007 Sept; 104(3): e8-e14.

• Dantrolene (Dantrium): Initial dosing at 25mg/day up to 400mg/day.• Action is peripheral via inhibition of the ryanodine receptor, the major calcium release

channel of the sarcoplasmic reticulum.

• Side effects: Drowsiness, sedation, weakness, fatigue, paresthesias, nausea and vomiting. Requires liver function monitoring.

• Diazepam (Valium): Dosing for non-neurological musculoskeletal disorders is 2mg BID up to 60mg.• Action by binding to benzodiazepine receptors on GABA receptors and increasing GABA

affinity for its receptor. Long half-life, CYP450 metabolism.

• Side effect: Due to a long half-life, drowsiness, confusion, dizziness, and trouble focusing. Potential for drug-drug interactions.

• Benzodiazepines primarily differ only in duration of action.

• Saletu A. On the pharmacology of sleep bruxism: placebo-controlled polysomnographic and pschometric studies with clonazepam. Neuropsychobiology. 2005; 51(4): 214-225.

Antidepressants

• This class of agents is used with the intent of behavior modification and alleviation of symptoms, and selection of a specific agent is based on current knowledge of the neurotransmitters, receptors, and neuronal circuits affected.1

• Specifically some of the drugs in this category are analgesic agents, which is a distinct pharmacologic property that is probably independent of their psychopharmacologic action. These analgesic effects can be differentiated from placebo, and may be seen at doses lower than those used for depression, and the effects will be seen in non-depressed patients.2,3

• These drugs generally do not serve as agonists to opioid receptors, and owing to their effects on serotonin and NE receptors, it suggests that blocking the reuptake of one or both of these neurotransmitters has an antinociceptive action.

1Stahl SM. From circuits to symptoms in psychopharmacology. In: Stahl SM, Ed. Stahl’s Essential Psychopharmacology. 3rd ed. New York: Cambridge University Press; 2008: 223-245.

2Iacovides A. Comorbid mental and somatic disorders: an epidemiological perspective. Curr Opin Psychiatry. 2008 Jul; 21(4): 417-421.

3Magni G. The use of antidepressants in the treatment of chronic pain. Drugs. 1991 Nov; 42(5): 730-738.

Medication FDA Approval Common off-label pain use

Dose

Anxiolytic medications

Diazepam Anxiety, preoperative sedation: alcohol withdrawal: muscle spasm: seizures

Treatment of anxiety-induced pain

Usual starting dose 2-10mg/day

Lorazepam Anxiety; insomnia; status epilepticus


Initial total daily dose should not exceed 2mg/day; can be less

Oxazepam Anxiety; alcohol withdrawal


Usual starting dose 10mg TID

Temazepam Insomnia Treatment of anxiety-induced pain

Typical starting dose for adults 7.5-15mg HS

Stimulant medications

Dextroamphetamine Narcolepsy Treatment of opioid-induced sedation

2.5-5mg BID

Modafinil Narcolepsy; OSA Treatment of opioid-induced sedation

Usual dose 200mg/day

Methylphenidate ADHD; Narcolepsy Treatment of opioid-induced sedation

5-15mg BID

Donepezil Alzheimer’s dementia

Used for chronic recalcitrant pain

Starting dose 5mg daily


Dose

TCA, tertiary amines

Amitriptyline Depression Neuropathic pain; fibromyalgia

Start at 10-25mg/day; increase by 10-25 mg/day up to 75-150mg/day

Imipramine Depression Neuropathic pain; fibromyalgia

Same

Doxepin Depression; anxiety

Neuropathic pain; fibromyalgia

Same

Clomipramine OCD Neuropathic pain; fibromyalgia

Same

TCA, secondary amines

Nortriptyline Depression Neuropathic pain; fibromyalgia

10mg HS, carefully titrated up to 75mg

Protriptyline Depression Neuropathic pain; fibromyalgia

15-40 mg/day, can be taken in one daily dose

Desipramine Depression Neuropathic pain; fibromyalgia

Starts at 100-200mg, either taken as a single dose or split into two equal doses/day


Dose

SNRI

Venlafaxine Major depression; anxiety

Neuropathic pain 75mg/day

Milnacipran Fibromyalgia Major depression; neuropathic pain

100-200mg/day

Duloxetine Major depression; diabetic neuropathy; anxiety disorder; fibromyalgia

Nondiabetic neuropathic pain

60mg QD-BID

Norepinephrine reuptake inhibitors

Bupropion Major depression; adjunctive in smoking cessation

Neuropathic pain (questionable)

100mg titrated up to 400mg/day in divided doses

Maprotiline Depression Chronic pain, neuropathic pain, and fibromyalgia

Initial dose 75mg daily in 2 or 3 divided doses


Dose

SSRI

Fluoxetine Major depression; OCD; panic, anxiety, and bipolar disorders

Fibromyalgia (weak) 20mg/day

Citalopram Major depression Neuropathic pain, fibromyalgia (weak)

20-40mg/day

Escitalopram Major depression; anxiety disorder

Neuropathic pain; fibromyalgia (weak)

20-40mg/day

Paroxetine Major depression; OCD; PTSD; anxiety and panic disorders

Diabetic neuropathy (weak)

Starting dose 10-20mg/day

Sertraline Major depression; OCD; panic disorder; PTSD

Neuropathic pain; fibromyalgia

Starting dose 50mg/day

Fluvoxamine OCD Neuropathic pain (questionable)

Starting dose 50mg/da

Serotonin Receptor Modulators

Nefazodone Major depression Chronic pain; neuropathic pain; fibromyalgia

Starting 200mg/day, administered in 2 divided doses

Trazodone Major depression Chronic pain, neuropathic pain; fibromyalgia

Starting dose 150mg/day

Antidepressants

• TCAs have the strongest evidence of an analgesic effect.• McQuay HJ. A systematic review of antidepressants in neuropathic pain. Pain.

1996 Dec; 68(2-3): 217-227.

• Cochrane Review of efficacy on antidepressants in neuropathic pain.• Saarto T. Antidepressants for neuropathic pain. Cochrane Database Syst Rev.

2007 Oct 17; (4): CD005454

• Includes NNT and NNH figures

• 2007 FDA warning for increased suicidal ideation in first 2 months of treatment in patients <25 years old. This was not seen in adults over 24, and adults over 65 had a decreased risk of suicidality.

• TCAs and SNRIs are more effective in treating pain than the SSRIs. The action on both serotonin and NE is the important distinction. The serotonergic pathway has both inhibitory and excitatory actions, thus increasing only serotonin is the proposed mechanism for the lower analgesic properties.

Antidepressants

• Tricyclic Antidepressants (TCAs)• Analgesic properties when used in nonmalignant pain.

• Onghena P Antidepressant-induced analgesia in chronic non-malignant pain: a meta-analysis of 39 placebo-controlled studies. Pain. 1992 May; 49(2): 205-219.

• Action by increasing the levels of serotonin and NE from the synaptic cleft.

• Divided into tertiary amines (amitriptyline, imipramine, doxepin, and clomipramine) and secondary amines (nortriptyline and desipramine).

• Have the ability to improve sleep as well

• Glassman AH Cardiovascular effects of therapeutic doses of tricyclic antidepressants. A review. Arch Gen Psychiatry. 1981 Jul; 38(7): 815-820. Potential for significant side effects, particularly cardiotoxicity. To be avoided in patients who have a history of significant heart disease.

Antidepressants

• Amitriptyline (Elavil): Starting dose typically 10-25mg HS, increasing 10-25mg/wk to 75-150mg/day

• Balanced serotonin and NE reuptake

• Side effects: Anticholinergic effects (dry mouth, postural hypotension, sedation, dry mouth, urinary retention) can develop rapidly but tolerance develops. Also potential weight gain.

• Sharav Y. The analgesic effect of amitriptyline on chronic facial pain. Pain. 1987 Nov: 3192): 199-209. Demonstrated low dose was as effective as a higher dose for orofacial pain.

• However, there are very few placebo-controlled studies in the literature examining the effects on orofacial pain.

• Raigrodski AJ. The Effect of Amitriptyline on Pain Intensity and Perception of Stress in Bruxers. J Prosthodont 2001; 10: 73-77. Did not reduce pain intensity in bruxers at 25mg HS for 4 weeks compared to placebo.

• Nortriptyline (Pamelor): Initial dosing at 10mg HS, increased after 3-5 days to 20mg HS, and then titrated.

• Fewer anticholinergic effects than amitriptyline, faster time to max dose. (active metabolite of amitryptiline)

• Relatively selective for NE reuptake

• Imipramine (Tofranil), Doxepin (Sinequan), Clomipramine (Anaframil), Protriptyline (Vivactil), Desipramine (Norpramin)• Desipramine is the least anticholinergic and sedating

• Mechanism of action and side effects basically similar to amitriptyline.

Antidepressants

• Selective Serotonin Reuptake Inhibitors (SSRIs)• Differ from TCAs in specific inhibition of presynaptic reuptake of

serotonin and lack of postsynaptic receptor blocking effects or membrane stabilization.

• Side effects: Reduced compared to other antidepressants, lower risk of interaction with other sedatives.

• Potent inhibitors of CYP P450 (except citalopram and escitalopram)

• Less effective than TCAs as migraine preventives and in treatment of TTH: • Moja PL. Selective serotonin reuptake inhibitors for preventing migraine and

tension-type headaches. Cochrane Database Syst Rev. 2005 Jul 20; (3): CD002919.

• Increased bruxism, particularly in the higher dose ranges. Case-reported basis with the need for further research for prevalence, risk factors, and causation.• Ellison JM. SSRI-associated nocturnal bruxism in four patients. J Clin Psychiatry.

1993 Nov; 54(11): 432-434.

• Romanelli F. Possible paroxetine-induced bruxism. Ann Pharmacother. 1996 Nov; 30(11): 1246-1248.

• Gerber PE. Selective serotonin-reuptake inhibitor-induced movement disorders. Ann Pharmacother. 1998 Jun; 32(6): 692-698.

• Lobbezoo F. Reports of SSRI-associated bruxism in the family physician’s office. J Orofac Pain. 2001 Fall; 15(4): 340-346.

Antidepressants

• Fluoxetine (Prozac): Typical dose is 5-20mg/day, can increase to max of 80mg/day BID• Goldenberg DL. A randomized double-blind crossover trial of fluoxetine and

amitriptyline in the treatment of fibromyalgia. Arthritis Rheum. 1996 Nov; 39(11): 1852-1859. Best analgesic effect of the group, but at higher doses, and improves when combined with other drugs.

• Citalopram (Celexa): Typical dose is 20mg/day to 40mg maximum• Highest selectivity for serotonin reuptake transporters

• Sertraline (Zoloft): Typical dose is 50mg/day to 200mg maximum

• Escitalopram (Lexapro): Typical dose is 10mg/day to 20mg maximum

• Paroxetine (Paxil): Typical dose is 20mg/day to 50mg/day maximum• Patkar AA. A randomized, controlled, trial of controlled-release paroxetine in

fibromyalgia. Am J Med. 2007 May; 120(5): 448-454. Weak effect on pain measures

• Fluvoxamine (Luvox): Typical dose is 50mg HS to 300mg maximum

Antidepressants

• Selective Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)• Lower side effect profile than TCAs.

• Stahl SM. SNRIs: their pharmacology, clinical efficacy, and tolerability in comparison with other classes of antidepressants. CNS Spectr. 2005 Sep; 10(9): 732-747.• Blocking reuptake of serotonin and NE with differing selectivity. Milnacipran blocks

with equal affinity, duloxetine has a 10-fold selectivity for 5-HT, venlafaxine a 30-fold.

• Similar efficacy for both anxiety disorders and chronic pain relief with or without depression.

• Tolerability differs, with venlafaxine the least tolerated, with duloxetine and milnacipran better tolerated and almost devoid of cardiovascular toxicity.

• Tapered to effective dose, tapered down when discontinuing

• Lack of studies on orofacial pain

• In use for pain relief, the prevailing concept is that increasing the available amounts of serotonin and NE may correct a functional deficit in the neurotransmission of the descending inhibitory pain pathways thereby reducing pain.

Antidepressants

• Duloxetine (Cymbalta): Typical dose at 60mg 1-2 times/day.• Has a strong metabolism-inhibitory effect on CYP P450, raising concerns

with drug interactions.

• Side effects of nauseau, dry mouth, constipation, diarrhea, and anorexia

• FDA notice in 2008 regarding overdose with alcohol use, encouraging using the smallest possible dose.

• Approved for use in Fibromyalgia

• Arnold LM. A double-blind, multicenter trial comparing duloxetine to placebo in the treatment of fibromyalgia patients with or without major depressive disorder. Arthritis Rheum. 2004 Sep; 50(9): 2974-2984.

• Venlafaxine (Effexor): Typical dose at 37.5mg BID, maximum at 375mg• Forssell H. Venlafaxine in the Treatment of Atypical Facial Pain: A

Randomized Controlled Trial. J Orofac Pain. 2004; 18: 131-137. Demonstrated a modest effect of Venlafaxine on pain relief but not intensity compared to placebo.

• Milnacipran (Savella): Typical dose 12.5mg/day to 12.5mg BID to QID to 50mg BID

Antidepressants

• Norepinephrine Reuptake Inhibitor

• Bupropion (Wellbutrin): Typical dose at 100mg/day, increasing to 200mg BID• Blocks reuptake of serotonin and dopamine

• Lower risk of sexual dysfunction and weight gain that TCAs.

• Often an alternative or adjunctive treatment for SSRI non-responders

• Side effects: Increased adverse effects of headache, tremor, and seizure

• Ineffective in pain relief in non-neuropathic pain

• Semenchuk MR. Double-blind, randomized trial of bupropion SR for the treatment of neuropathic pain. Neurology. 2001 Nov 13; 57(9): 1583-1588. Some benefit in neuropathic pain

• Serotonin receptor modulator• No accepted dosing for use in pain

• Typically used for treatment of depression and related insomnia

• Often used as an adjunct with SSRI or SNRI to signficantly increase serotonin levels while avoiding side effects in primary drug. Potential effect on mu-opioid receptor expression.

• Less anticholinergic that TCAs, but potential for similar side effects still possible.• Trazadone (Desyrel): Typical dose for insomnia 25-50mg HS

• Nefazodone (Serzone): Less commonly used due to risk of hepatotoxicity and sedation

Anxiolytics/Hypnotics

• Primarily Benzodiazepines

• Divided into duration of effect

• Side effects: Drowsiness, confusion, trouble concentrating, and dizziness. Also this class is metabolized by the CYP P450 pathway (except lorazepam, oxazepam, and temazepam).

• Patients with chronic pain have elevated levels of anxiety

• No evidence that one particular benzodiazepine is more effective if adequate dose is given.

• Primary site of action is increasing affinity for GABA-A receptor subtype, and possibly the NO pathway.• Jimenez-Velazquez G. Participation of the GABA/benzodiazepine receptor and

the NO-cyclicGMP pathway in the antinociceptive-like effrects of diazepam. Pharmacol Biochem Behav. 2008 Nov; 91(1): 128-133.

• Campo-Soria C. Mechanism of action of benzodiazepines of GABA A receptors. Br J Pharmacol. 2006; 148(7): 984-990.


• Minimal publications on antinociceptive use of this class of drug.

• Potential benefit in neuropathic pain conditions: Particularly clonazepam either used topically or in an oral dissolvable form.• Graff-Radford SB. Facial Pain. Current Op Neuro. 2000 June; 13(3): 291-296.

• Mellis M. Atypical Odontalgia: A Review of the Literature. Headache. 2003 November; 43(10): 1060-1074.

• Singer E. A controlled evaluation of ibuprofen and diazepam for chronic orofacial muscle pain. J Orofac Pain. 1997 Spring; 11(2): 139-146.• Demonstrated a significant drug effect of diazepam on muscle pain over placebo and

ibuprofen.

• Dellemijn PLI. Do benzodiazepines have a role in chronic pain management? Pain. 1994; 57: 137-152.• Concluded chronic use of benzodiazepines is effective for some musculoskeletal pain.

• Potential use in negating SSRI-induced bruxing behavior.• Saletu A. On the pharmocotherapy of sleep bruxism: placebo-controlled

polysomnographic and psychometric studies with clonazepam. Neuropsychobiology. 2005; 51(4): 214-225.

• Bostwick JM. Buspirone as an antidote to SSRI-induced bruxism in 4 cases. J Clin Psychiatry. 1999 Dec; 60(12): 857-860.


Long Half-Life Medium Half-Life Short Half-Life

Diazepam Lorazepam Alprazolam

Flurazepam Temazepam Oxazepam

Clonazepam Estazolam Triazolam

Prazepam

Chlordiazepoxide

Clorazepate

Benzodiazepine Equivalency Chart


• Long half-life:

• Diazepam (Valium): Typical dose 2-10mg HS, or TID/QID

• Flurazepam (Dalmane): Typical dose 15-30mg HS

• Clonazepam (Klonopin): Typical dose 0.5-2mg HS, or TID/QID

• Prazepam (Centrax): Typical dose 10mg HS or TID

• Chordiazepoxide (Librium): Typical dose 5-25mg HS or TID

• Clorazepate (Tranxene): 7/5-15mg HS or BID


• Medium half-life:

• Lorazepam (Ativan): Typical dose 0.5-2mg HS or BID/TID

• Temazepam (Restoril): Typical dose 15-30mg HS

• Estazolam (ProSom): Typical dose 1-2mg HS or BID


• Short half-life:

• Alprazolam (Xanax): Typical dose 0.25-0.5mg HS or TID/QID

• Oxazepam (Serax): Typical dose 10-25mg HS or TID/QID

• Triazolam (Halcion): Typical dose 0.125-0.5mg HS

• Other:

• Choral Hydrate (Noctec): Typical dose 2.5-5mg/kg up to 1000mg HS

• Trazadone (Desyrel): Typical dose 25-50mg HS for insomnia• 50-100mg BID/TID for depression to

maximum of 400mg

• Zolpidem (Ambien): Typical dose 5-10mg HS

• Zaleplon (Sonata): Typical dose 5-10mg HS

• Eszoplicone (Lunesta): 2-3mg HS

• Buspirone (Buspar): 20-30mg/day divided BID/TID (start at 7.5mg/day BID)


• Anticholinergic:

• Diphenhydramine (Benadryl): Typical dose 25-50mg HS or q6H

• Hydroxyzine (Atarax/Vistaril): 50-100mg HS or TID/QID

Topicals

• Advantages over systemic medications: More likely to be accepted as a viable treatment in the highly anxious and nocebo-responsive patient, and a generalized lack of drug interactions and side effects.

• Still need avoidance in patients who cannot tolerate any of the ingredients, are severely asthmatic, severe liver or kidney disease, history of methemoglobinemia, and skin disorders or wounds.

• Can be useful in neuropathic pain conditions, particularly those that are responsive to peripheral application of local anesthetic.

• Most common are anesthetics and analgesics.

• These anesthetics result in a diminished propagation of nociceptive signals along the sensory neuron by blocking sodium channels, and the analgesics via a local decreased production of inflammatory mediators in the tissue where they are applied.

Topicals

• Topical anesthetics (Lidocaine, Benzocaine, Prilocaine)

• Topical analgesics (Aspercreme, Voltaren, Emugel)

• Capsaicin• Acts by depleting Substance P from sensory nerves, possibly

degenerating epidermal nerve fibers, action on VR1 receptor to open Ca channels and depolarize C-fibers.

• Available in 0.025% and 0.075%

• Most frequent side effect is burning at the site of application

• Can take several weeks for genuine benefit to be realized

• Typically used as an adjuvant therapy, not a first-line standalone therapy

• Mason L. Systematic Review of topical capsaicin for the treatment of chronic pain. BMJ 2004; Apr 24; 328(7446): 991 Epub March 19, 2004

Topicals

• Sympathomimetic Agents (Clonidine):• Can be useful in chronic neuropathic conditions where sympathetic

activity is stimulating upregulated alpha-1 adrenergic receptors on injured C-fibers via NE release. Clonidine interrupts the release of the NE.

• Side effect potential so low dose is required

• Epstein JB. Topical clonidine for orofacial pain: a pilot study. J Orof Pain. 1997 Fall; 11(4): 346-352.

• Jorge LL. Topical preparations for pain relief: efficacy and patient adherence. J Pain Res 2011; 4: 11-24.

• NMDA Blocking Agents (Ketamine):• Acts on the peripheral NMDA receptors, and also has analgesic actions via

blocking volatage-sensitive Ca2 channels, altering cholinergic and monoaminergic actions, interacting with opioid mechanisms.

• Side effect potential so low dose is required

• Mathisen LC. Effect of ketamine, an NMDA receptor inhibitor, in acute and chronic orofacial pain. Pain. 1995; 61: 215-220.

• Lynch ME. Topical 2% Amitryptiline and 1% Ketamine in neuropathic pain syndromes: a randomized, double-blinded, placebo-controlled trial. Anesthesiology. 2005 Jul; 103(1): 140-146.

Topicals

• Padilla M. Topical Medications for Orofacial Neuropathic Pain: A Review. JADA 2000 February; 131: 184-195.

• Stanos SP. Topical Agents for the Management of Musculoskeletal Pain. Journal of Pain and Symptom Management. 2007 March; 33(3): 342-355.

• Jorge LL. Topical preparations for pain relief: efficacy and patient adherence. J Pain Res 2011; 4: 11-24.

Topicals

Padilla M. Topical Medications for Orofacial Neuropathic Pain: A Review. JADA 2000 February; 131: 184-195.

Topicals

• Multiple compounded agents:

Injectables

• Primarily local anesthetics

• Act to selectively block sodium channels in the nerve fibers and increase the threshold for spontaneous firing.

• Typically dental anesthetic agents are used, 2% Lidocaine is most common agent.

• Used for diagnostic and therapeutic purposes

• In neuropathic conditions, lack of response to local infiltration leads to an assumption of a more centralized condition. Can also provide relief to TN.

• Sanders M. Efficacy of sphenopalatine ganglion blockade in 66 patients suffering from cluster headache: a 12- to 70-month follow-up evaluation. J Neurosurg 1997;87:876–880. Used for autonomic activity via the Sphenopalatine ganglion and Stellate ganglion.

• Temporomandibular joint anesthesia via an Auriculotemporal nerve block

• Occipital nerve block and Cervical plexus blocks for referred pain issues

Injectables

• Trigger point injections: Cummings TM. Needling therapies in the management of myofascial trigger point pain: a systematic review. Arch Phys Med Rehabil. 2001; 82(7): 986-992.• Kim PS. Role of injection therapy: review of indications for trigger point

injections, regional blocks, facet joint injections, and intra-articular injections. Curr Opin Rheum. 2002; 14(1): 52-57.

• Botox for trigger points, muscle spasm, dystonias, trigeminal neuralgia, and chronic migraine.• Graboski CL. Botulinum toxin A versus bupivicaine trigger point injections

for the treatment of myofascial pain syndrome: A randomised double blind crossover study. Pain. 2005 November; 118 (1-2): 170-175.

• Diener HC. OnabotuninumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia. 2010 July; 30(7): 804-814.

• Wu CJ. Botulinum toxin type A for the treatment of trigeminal neuralgia: results from a randomized, double-blind, placebo-controlled trial. 2012 April 5 (online epub).

• Costa J. Botulinum toxin type A therapy for cervical dystonia. Cochrane Database of Systematic Reviews 2005, Issue 1. Art. No.: CD003633.

Cannabis• Has demonstrated efficacy in neuropathic pain, but small studies

thus far.

• Appears to have a positive interactive effect with opioids, and analgesic effects alone. Method of ingestion may limit effectiveness.

• Questions surrounding rating dependence issues for other drug trials

• Care needed to distinguish between proper use, recreational use, and self-medication use.

• McQuay HJ. More evidence cannabis can help in neuropathic pain. CMAJ 2010 October; 182(14): 1494-1495.

• Lynch ME. Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. Br Journal Cl Pharm 2011; 72(5):735-744.

• Abrams DI. Cannabinoid-Opioid Interaction in Chronic Pain. Cl Pharm Therap 2011 December; 90(6): 844-851.

• Finnerup NB. The evidence for pharmacological treatment of neuropathic pain. Pain 2010; 150: 573-581.

Literature support

• Martin WJ, Forouzanfar T. The Efficacy of Anticonvulsants on Orofacial Pain: A Systematic Review. Oral Surg Oral Med Oral Path Oral Rad Endo 2011; 111: 627-633.• Searched PubMed, Cochrane, and Ovid Medline databases from

1962 through March 2010. 8 useful trials were identified. 4 were classified as high quality.

• Heterogeneity and small sample sizes precluded drawing definitive conclusions.

• Conclusion: There is limited to moderate evidence supporting the efficacy of anticonvulsants for the treatment of patients with orofacial pain disorders.

• Cascos-Romero J, Vazquez-Delgado E. The Use of Antidepressants in the Treatment of Temporomandibular Joint Disorders: Systematic Review of the Literature of the Last 20 Years. Oral Patol Oral Cir Bucal 2009; 14(1): 3-7.• Searched from 1988 through 2008. Medline and Cochrane

databases.

• 11 articles, 7 of which were literature reviews.

• Conclusion: Level B scientific evidence for using TCAs in orofacial pain patients.

• Mujakperuo HR, Watson M, Morrison R. Pharmacological interventions for pain in patients with temporomandibular disorders. A Cochrane Review 2010; 10.• 11 studies with a total of 496 subjects. Primary outcome

studied was pain.

• Conclusions: There is insufficient evidence to support or not support the effectiveness of the reported drugs for the management of pain due to TMD. There is a need for high quality RCTs to derive evidence of the effectiveness of pharmacological interventions to treat pain associated with TMD.

• List T, Axelsson S. Pharmacologic Interventions in the Treatment of Temporomandibular Disorders, Atypical Facial Pain, and Burning Mouth Syndrome. A Qualitative Systematic Review. J Orofac Pain 2003; 17: 301-310.• Selection based on RCTs, adult subjects, TMD, RA of TMJ, AFP, or

BMS and a pain duration of over 3 months. Searched Medline, Cochrane, Embase, and PsychLitt.

• 11 studies met criteria with 368 subjects. 4 trials on TMD, 2 on AFP, 1 on BMS, 1 on RA of TMJ, and 3 on mixed groups with TMD/AFP.

• Conclusions: The common use of analgesics in TMD, AFP, and BMS is not supported by scientific evidence. More large RCTs are needed to determine which pharmacologic interventions are effective.

• Hersh EV, Balasubramaniam R. Pharmacologic Management of Temporomandibular Disorders. Oral Maxillofacial Surg Clin N Am 20. 2008; 197-210.

• Dionne RA. Pharmacologic treatments for temporomandibular disorders. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997; 83: 134-42.

• Ganzberg S. Pain Management Part II: Pharmacologic Management of Chronic Orofacial Pain. Anesth Prog 2010; 57: 114-119.

• Attal N, Cruccu G. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. European Journal of Neurology 2010; 17: 1113-1123.

Thank You

Pharmacology in Orofacial Pain Robert W Mier DDS, MS Tufts University School of Dental Medicine.

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Transcript of Pharmacology in Orofacial Pain Robert W Mier DDS, MS Tufts University School of Dental Medicine.