Pharmacology in Orofacial Pain

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

Pharmacologic Targets: A Mechanistic Approach
Pain Perception: opioids, α2-agonists, TCAs, SSRIs, SNRIs Modulation: TCAs, SSRIs, SNRIs Ascending input Descending modulation Dorsal horn Transmission: LAs, opioids, α2-agonists Dorsal root ganglion It is often necessary to employ a mechanistic approach to drug selection, with less emphasis on therapeutic class stratification and more attention to efficacy related to the underlying cause.11,12 This may allow for rational polymodal selection of therapeutic agents and improved patient outcomes12 Opioids, tramadol, tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors can enhance the descending inhibitory pathways from the brain Opioids activate receptors that result in reducing the release of neurotransmitters (eg, norepinephrine, glutamate, serotonin, substance P, acetylcholine)11 Some antidepressants inhibit reuptake of biogenic amines (eg, norepinephrine, serotonin). Tricyclic antidepressants are strong sodium-channel modulators10 Two groups of agents modulate central sensitization at the spinal cord: Drugs that inhibit calcium flux, such as anticonvulsants Drugs that affect N-methyl-D-aspartate (NMDA) receptors. This second group contains agents whose primary indications are unrelated. These drugs modulate central sensitization via effects on NMDA receptors and are still under study for analgesic use11 Drugs that modulate peripheral sensitization by inactivating voltage-dependent sodium channels include carbamazepine, oxcarbazepine, topiramate, and lidocaine. Gabapentin has no effect on Na+ channels; however, it inhibits Ca++ channel current in a voltage-dependent manner. Capsaicin acts at vanilloid receptors, causing initial short-term receptor activation followed by long-term Ca++-dependent desensitization12 Topical analgesic patches offer some advantages over oral agents, the primary one being reduced systemic side effects7 Medication administration via the patch helps avoid chemical or metabolic degradation of the agent in the gastrointestinal tract The patch can also be removed easily from the skin to limit adverse events if they occur Removal of the patch will halt drug infiltration Spinothalamic tract Transmission: LAs, opioids Peripheral nerve Trauma Transduction: LAs, capsaicin, anticonvulsants, NSAIDs, ASA, acetaminophen, nitrate Peripheral nociceptors 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:

Nociceptive vs Neuropathic Pain
Initiated or caused by primary lesion or dysfunction in the nervous system Responsive to neuromodulators May require poly- pharmacotherapy Nociceptive1,2 Caused by activity in neural pathways in response to stimuli potentially damaging to tissue Responsive to analgesics Mixed Caused by both primary injury and secondary effects May require poly- pharmacotherapy Pain may be classified as nociceptive, neuropathic, or mixed Nociceptive pain results from activity in neural pathways caused by stimuli that are potentially damaging to tissue2,4 Examples include postoperative pain, mechanical low back pain, sickle cell crisis, and sports or exercise injuries Also included are chronic pain such as arthritis and some types of cancer pain Neuropathic pain is caused by a primary lesion or dysfunction in the peripheral and/or central nervous systems2,5,6 Examples of peripheral neuropathic pain include: Human immunodeficiency virus–related sensory neuropathy Postherpetic neuralgia Painful diabetic neuropathy Stump pain Examples of central neuropathic pain include: Central poststroke pain Spinal cord injury pain Trigeminal neuralgia Multiple sclerosis pain Phantom limb pain Mixed pain occurs when components of continued nociceptive pain coexist with a component of neuropathic pain Migraine headaches may represent a mixture of neuropathic and nociceptive pain Also included are myofascial pain and low back pain 1. International Association for the Study of Pain. IASP pain terminology. Available at: Neuropathic%20pain. Accessed March 9, Portenoy RK, Kanner RM, eds. Pain Management: Theory and Practice. Philadelphia, Pa: FA Davis Co; 1996; NPC/JCAHO. Pain: Current Understanding of Assessment, Management, and Treatments. December 2001.

Polypharmacy Treat adverse effects of primary drug
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 ;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 postherpetic 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

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

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

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
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 Summarized from WHO acute pain management guidelines

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):

Opioids Chou R. Clinical Guidelines for the Use of Chronic Opioid Therapy in Chronic Noncancer Pain. Pain February; 10(2): 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 February; 10(2): 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 ; 22: 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: 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: 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): 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 Sep; 32(3): 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 Dec; 3(4): Proposed guidelines that support the chronic use of opioids for chronic nonmalignant pain.

Opioid Metabolism 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.

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
Amelioration Constipation 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 The major side effects of opioid analgesics are well known and include constipation, nausea, vomiting, dizziness, sedation, cognitive dysfunction, itching, sweating, and respiratory depression10 Clinical experience suggests that many of these effects resolve over time, although this has not been carefully studied. However, side effects are the reason that many patients discontinue therapy10,11 Patients who continue opioid therapy and are affected by these side effects may be suffering needlessly. Many of these side effects can be prevented and treated, which will optimize therapy10 The best approach to prevent opioid-related side effects is to gradually titrate the dose and to consider prophylaxis (eg, constipation)10 Finally, because the side effects of opioids are idiosyncratic, switching opioids can eliminate or improve side effects in any given patient10 McNicol E et al. J Pain. 2003;4:

OPIOID ANALGESICS Recommended Codeine Dihydrocodeine Hydrocodone
Oxycodone Morphine Oxymorphone Hydromorphone Levorphanol Methadone Fentanyl *Tramadol (Ultram) *Tapentadol (Nucynta)

Opioid Equivalency Table

OPIOID ANALGESICS Not Recommended Propoxyphene (Darvon)
Pentazocine (Talwin) Meperidine (Demerol) Partial agonists (Buprenorphine) Agonist-antagonists (Butorphanol)

Opioid Tolerance and Opioid Induced Hyperalgesia
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

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:CD

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 mg 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: mg, 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): 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: Very poor data for use in chronic pain aside from RA Naproxen: mg to start, then 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 Sep; 111(1-2): 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: mg q6-8h, maximum 400mg/day Piroxicam (Feldene): mg/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): Ekberg EC. Diclofenac sodium as an alternative treatment of TMJ pain. Acta Odont Scand June; 54(3): Kubitzek F. Analgesic efficacy of low-dose diclofenac versus paracetamol and placebo in postoperative dental pain. J Orofac Pain 2003; 17(3): Nabumetone (Relafen): mg/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): mg BID. Recommended for osteoarthritis, no data on myogenous pain. Use in orofacial pain studied in Ta and Dionne. Meloxicam (Mobic): mg qd. Slow onset and may take time for benefit to be realized. Etodolac (Lodine): mg 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 mg 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):

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 Feb; 105(2):

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

Carbamazepine (Tegretol): 200mg BID, titrated to effective range of mg/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 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): 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 mg/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 Oct; 16(10):

Lamotrigine (Lamictal): mg/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 Oct;34(4): 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 Dec; 17)4):

Pregabalin (Lyrica): mg/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 Sep; 64(9): Baclofen (Lioresal): 5-10mg HS to start, increasing by 5mg each week and titrated up to mg 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 : 9:

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 Apr; 4(4): Topiramate (Topamax): Initial dosing at 25mg BID, increasing 50mg/week to effective range of mg/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 Nov: 31(2): 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 Jun; 53(6): See S. Skeletal muscle relaxants. Pharmacotherapy Feb; 28(2): 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 Aug; 28(2): 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 ; 16(1): Borenstein DG. Efficacy of a low-dose regimen of cyclobenzaprine hydrochloride in acute skeletal muscle spasm: results of two placebo-controlled trials. Clin Ther ; 25:

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): mg 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 Dec; 11(6): 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 ; 52(3):

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 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 ; 51(4):

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: 2Iacovides A. Comorbid mental and somatic disorders: an epidemiological perspective. Curr Opin Psychiatry Jul; 21(4): 3Magni G. The use of antidepressants in the treatment of chronic pain. Drugs Nov; 42(5):

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 Typical starting dose for adults mg HS Stimulant medications Dextroamphetamine Narcolepsy Treatment of opioid- induced sedation 2.5-5mg BID Modafinil Narcolepsy; OSA Usual dose 200mg/day Methylphenidate ADHD; Narcolepsy 5-15mg BID Donepezil Alzheimer’s dementia Used for chronic recalcitrant pain Starting dose 5mg daily

Medication FDA Approval Common off-label pain use Dose TCA, tertiary amines Amitriptyline Depression Neuropathic pain; fibromyalgia Start at 10-25mg/day; increase by mg/day up to mg/day Imipramine Same Doxepin Depression; anxiety Clomipramine OCD TCA, secondary amines Nortriptyline 10mg HS, carefully titrated up to 75mg Protriptyline 15-40 mg/day, can be taken in one daily dose Desipramine Starts at mg, either taken as a single dose or split into two equal doses/day

Medication FDA Approval Common off-label pain use Dose SNRI Venlafaxine Major depression; anxiety Neuropathic pain 75mg/day Milnacipran Fibromyalgia Major depression; neuropathic pain mg/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

Medication FDA Approval Common off-label pain use 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) 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 Chronic pain; neuropathic pain; fibromyalgia Starting 200mg/day, administered in 2 divided doses Trazodone 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 Dec; 68(2-3): Cochrane Review of efficacy on antidepressants in neuropathic pain. Saarto T. Antidepressants for neuropathic pain. Cochrane Database Syst Rev 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 May; 49(2): 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 Jul; 38(7): 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 mg/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 Nov: 3192): 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: 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 Jul 20; (3): CD 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 Nov; 54(11): Romanelli F. Possible paroxetine-induced bruxism. Ann Pharmacother Nov; 30(11): Gerber PE. Selective serotonin-reuptake inhibitor-induced movement disorders. Ann Pharmacother Jun; 32(6): Lobbezoo F. Reports of SSRI-associated bruxism in the family physician’s office. J Orofac Pain Fall; 15(4):

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 Nov; 39(11): 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 May; 120(5): 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 Sep; 10(9): 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 Sep; 50(9): 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 ; 18: 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 Nov 13; 57(9): 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 Nov; 91(1): Campo-Soria C. Mechanism of action of benzodiazepines of GABA A receptors. Br J Pharmacol ; 148(7):

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 June; 13(3): Mellis M. Atypical Odontalgia: A Review of the Literature. Headache November; 43(10): Singer E. A controlled evaluation of ibuprofen and diazepam for chronic orofacial muscle pain. J Orofac Pain Spring; 11(2): 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 ; 57: 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 ; 51(4): Bostwick JM. Buspirone as an antidote to SSRI-induced bruxism in 4 cases. J Clin Psychiatry Dec; 60(12):

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 mg HS or TID/QID Oxazepam (Serax): Typical dose 10-25mg HS or TID/QID Triazolam (Halcion): Typical dose mg 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): mg/day divided BID/TID (start at 7.5mg/day BID)

Anticholinergic: Diphenhydramine (Benadryl): Typical dose 25-50mg HS or q6H Hydroxyzine (Atarax/Vistaril): mg 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 Fall; 11(4): Jorge LL. Topical preparations for pain relief: efficacy and patient adherence. J Pain Res 2011; 4: 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. Mathisen LC. Effect of ketamine, an NMDA receptor inhibitor, in acute and chronic orofacial pain. Pain. 1995; 61: Lynch ME. Topical 2% Amitryptiline and 1% Ketamine in neuropathic pain syndromes: a randomized, double-blinded, placebo-controlled trial. Anesthesiology Jul; 103(1):

Topicals Padilla M. Topical Medications for Orofacial Neuropathic Pain: A Review. JADA 2000 February; 131: Stanos SP. Topical Agents for the Management of Musculoskeletal Pain. Journal of Pain and Symptom Management March; 33(3): Jorge LL. Topical preparations for pain relief: efficacy and patient adherence. J Pain Res 2011; 4:

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

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 ; 82(7): 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 ; 14(1): 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 November; 118 (1-2): Diener HC. OnabotuninumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia July; 30(7): Wu CJ. Botulinum toxin type A for the treatment of trigeminal neuralgia: results from a randomized, double-blind, placebo-controlled trial April 5 (online epub). Costa J. Botulinum toxin type A therapy for cervical dystonia. Cochrane Database of Systematic Reviews 2005, Issue 1. Art. No.: CD

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 October; 182(14): Lynch ME. Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. Br Journal Cl Pharm 2011; 72(5): Abrams DI. Cannabinoid-Opioid Interaction in Chronic Pain. Cl Pharm Therap December; 90(6): Finnerup NB. The evidence for pharmacological treatment of neuropathic pain. Pain 2010; 150:

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: Searched PubMed, Cochrane, and Ovid Medline databases from through March 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
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 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
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: 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
Hersh EV, Balasubramaniam R. Pharmacologic Management of Temporomandibular Disorders. Oral Maxillofacial Surg Clin N Am ; Dionne RA. Pharmacologic treatments for temporomandibular disorders. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997; 83: Ganzberg S. Pain Management Part II: Pharmacologic Management of Chronic Orofacial Pain. Anesth Prog 2010; 57: Attal N, Cruccu G. EFNS guidelines on the pharmacological treatment of neuropathic pain: revision. European Journal of Neurology 2010; 17:

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