Pharm in Orofacial Pain Final

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
Perception: opioids,
±2-agonists, TCAs,
SSRIs, SNRIs
Pain
Ascending input
Descending modulation
Dorsal
horn
Modulation: TCAs,
SSRIs, SNRIs
Transmission: LAs,
opioids, ±2-agonists
Dorsal root ganglion
Spinothalamic
tract
Peripheral
nerve
Trauma
Peripheral nociceptors
Transmission: LAs, opioids
Transduction: LAs, capsaicin,
anticonvulsants, NSAIDs,
ASA, acetaminophen, nitrate
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.
Nociceptive vs Neuropathic Pain
Neuropathic1,3
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 polypharmacotherapy
• Initiated or caused
by primary lesion
or dysfunction in
the nervous system
• Responsive to
neuromodulators
• May require polypharmacotherapy
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.
Polypharmacy
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 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.
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. WileyBlackwell. 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
30 Most Common Orofacial Pain Diseases
•
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
30 Most Common Orofacial Pain Diseases
•
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): 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 asneeded 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 selfadministration 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.
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
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/ Switch opioids; endocrine monitoring;
reduced libido
testosterone replacement; endocrine consultation
Edema and sweating
Switch opioids
Dizziness
Antivertiginous agents (eg, scopolamine)
Confusion
Titrate dose; switch opioids
McNicol E et al. J Pain. 2003;4:231-256.
OPIOID ANALGESICS
Recommended
•
Codeine
• Morphine
•
Dihydrocodeine
• Oxymorphone
•
Hydrocodone
• Hydromorphone
•
Oxycodone
• 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 pronociceptive 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:CD004257.
Non-opioid analgesics
•
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. Longterm use the maximum is 600mg/day. 10-fold selectivity for Cox-2.
Non-opioid analgesics
•
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. Coadministration 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.
Anticonvulsants/Antiepileptics
•
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.
Anticonvulsants/Antiepileptics
•
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 5075mg 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.
Anticonvulsants/Antiepileptics
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.
Anticonvulsants/Antiepileptics
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 nondepressed 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
3rd
SM. From circuits to symptoms in psychopharmacology. In: Stahl SM, Ed. Stahl’s Essential Psychopharmacology.
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 anxietyinduced pain
Usual starting dose 210mg/day
Lorazepam
Anxiety; insomnia;
status epilepticus
Treatment of anxietyinduced pain
Initial total daily dose
should not exceed
2mg/day; can be less
Oxazepam
Anxiety; alcohol
withdrawal
Treatment of anxietyinduced pain
Usual starting dose 10mg
TID
Temazepam
Insomnia
Treatment of anxietyinduced pain
Typical starting dose for
adults 7.5-15mg HS
Dextroamphetamine
Narcolepsy
Treatment of opioidinduced sedation
2.5-5mg BID
Modafinil
Narcolepsy; OSA
Treatment of opioidinduced sedation
Usual dose 200mg/day
Methylphenidate
ADHD; Narcolepsy
Treatment of opioidinduced sedation
5-15mg BID
Donepezil
Alzheimer’s dementia
Used for chronic
recalcitrant pain
Starting dose 5mg daily
Stimulant medications
Medication
FDA Approval
Common off-label pain use
Dose
TCA, tertiary amines
Amitriptyline
Depression
Neuropathic pain;
fibromyalgia
Start at 10-25mg/day;
increase by 10-25
mg/day up to 75150mg/day
Imipramine
Depression
Neuropathic pain;
fibromyalgia
Same
Doxepin
Depression; anxiety
Neuropathic pain;
fibromyalgia
Same
Clomipramine
OCD
Neuropathic pain;
fibromyalgia
Same
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
TCA, secondary amines
Medication
FDA Approval
Common off-label pain use
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
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
Norepinephrine reuptake
inhibitors
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)
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
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
Serotonin Receptor
Modulators
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 metaanalysis 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): 12461248.
•
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 NOcyclicGMP 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.
Anxiolytics/Hypnotics
•
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.
•
•
•
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.
•
•
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.
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.
Anxiolytics/Hypnotics
Long Half-Life
Medium Half-Life
Short Half-Life
Diazepam
Lorazepam
Alprazolam
Flurazepam
Temazepam
Oxazepam
Clonazepam
Estazolam
Triazolam
Prazepam
Chlordiazepoxide
Clorazepate
Benzodiazepine Equivalency Chart
Anxiolytics/Hypnotics
•
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
Anxiolytics/Hypnotics
•
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
Anxiolytics/Hypnotics
•
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)
Anxiolytics/Hypnotics
•
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 selfmedication 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):735744.
•
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