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2. Adjuvant Analgesics
• Defined as drugs with other indications
that may be analgesic in specific
circumstances
• Numerous drugs in diverse classes
• Sequential trials are often needed
5. Multipurpose Adjuvant Analgesics
Antidepressants
• Best evidence: 30 amine TCAs (eg, amitriptyline)
• 20 amine TCAs (desipramine, nortriptyline) better
•
tolerated and also analgesic
Some evidence for SSRI/SSNRIs/atypical
antidepressants (eg, paroxetine, venlafaxine,
maprotiline, bupropion, others) and these are
better tolerated yet
6. Multipurpose Adjuvant Analgesics
Alpha-2 adrenergic agonists
• Clonidine and tizanidine used for chronic pain of
•
•
any type
Tizanidine usually better tolerated
Tizanidine starting dose 1–2 mg/d; usual
maximum dose up to 40 mg/d
7. Adjuvant Analgesics for Neuropathic Pain
Class
Examples
Anticonvulsants
gabapentin, valproate,
phenytoin, carbamazepine,
clonazepam, topiramate,
lamotrigine, tiagabine,
oxcarbazepine, zonisamide,
levetiracetam
Local anesthetics
mexiletine, tocainide
9. Adjuvant Analgesics for Neuropathic Pain
Anticonvulsants
• Gabapentin commonly used
– Favorable safety profile and positive RCTs in PHN/diabetic
neuropathy
– Usual effective dose: 600–3600 mg/d and sometimes higher
• Analgesic effects established for phenytoin,
•
carbamazepine, valproate, clonazepam, and
lamotrigine
Limited experience with other drugs
10. Adjuvant Analgesics for Neuropathic Pain
• Local anesthetics
• Oral therapy with mexiletine, tocainide,
flecainide
• IV/SQ lidocaine also useful
• Useful for any type of neuropathic pain
11. Adjuvant Analgesics for Neuropathic Pain
Miscellaneous drugs
• Calcitonin
– RCTs in CRPS and phantom pain
– Limited experience
• Baclofen
– RCT in trigeminal neuralgia
– 30–200 mg/d or higher
– Taper before discontinuation
12. Adjuvant Analgesics for Neuropathic Pain
NMDA-receptor antagonists
• N-methyl-D-aspartate receptor involved in
•
neuropathic pain
Commercially-available drugs are analgesic:
ketamine, dextromethorpan, amantadine
13. Topical Adjuvant Analgesics
• Used for neuropathic pain
– Local anesthetics
• Lidocaine patch
• Cream, eg, lidocaine 5%, EMLA
• Capsaicin
• Used for musculoskeletal pains
• NSAIDs
14. Adjuvant Analgesics for
Musculoskeletal Pain
“Muscle relaxants”
• Refers to numerous drugs, eg,
cyclobenzaprine, carisoprodol,
orphenadrine, methocarbamol,
chlorzoxazone, metaxalone
• Centrally-acting analgesics
• Do not relax skeletal muscle
The adjuvant analgesic drugs include many drugs in diverse classes. All of these drugs are available for indications other than analgesia, but they may be analgesic in select circumstances. The term “adjuvant” applies in the management of pain associated with advanced medical illness, in which case they are typically added to an opioid regimen. Overall, the term is a misnomer because these drugs now are commonly used as primary analgesics in many painful disorders.
Based on clinical observations, the adjuvant analgesics can be divided into a group that would be appropriate to consider for any type of pain, a group used generally for neuropathic pain, a group used for musculoskeletal pains, a group used for cancer pain, and a group used for headache prophylaxis.
Several classes of drugs have analgesic effects established in diverse pain syndromes and, on this basis, may be considered nonspecific analgesics. The antidepressants and the alpha-2 adrenergic agonists may be considered in this context. Corticosteroids probably are nonspecific analgesics also, but they are generally reserved for select patients because of their long-term toxicity.
Extensive evidence demonstrates the analgesic efficacy of antidepressant drugs. Evidence is best for the tricyclic drugs, but some of the newer drugs have been studied, may be analgesic, and are better tolerated.
Alpha-2 adrenergic agonists appear to have analgesic potential in all types of chronic pain. Tizanidine is available commercially as an antispasticity agent and may be better tolerated. For both tizanidine and clonidine, initial doses should be low, and the dose should be slowly titrated to judge analgesic effects.
In addition to the antidepressants and alpha-2 adrenergic agonists, a variety of other drug classes have been used for neuropathic pain. These include anticonvulsants, local anesthetics, and others.
Other drugs for neuropathic pain include the NMDA receptor antagonists and a variety of topical agents.
Anticonvulsants may be used to treat all types of neuropathic pain. Experience with gabapentin is extensive and favorable. Many other drugs with diverse mechanisms also are used. Patients with refractory neuropathic pain are candidates for sequential trials of these drugs, as an effort is made to identify the most favorable one.
Systemic local anesthetics can have an analgesic effect on all types of neuropathic pain. Both oral therapy and brief infusions of parenteral anesthetics have been used for pain.
Calcitonin, usually tried via the intranasal route, has been demonstrated to be analgesic in small studies of patients with complex regional pain syndrome (reflex sympathetic dystrophy) and acute phantom pain. On this basis, a trial may be indicated in refractory neuropathic pain. Baclofen is established as an analgesic for trigeminal neuralgia and also is tried for other types of neuropathic pain. The effective dose range is very broad. The potential for seizures upon drug withdrawal mandates dose tapering prior to discontinuation.
The NMDA receptor is involved in mechanisms responsible for some types of neuropathic pain. The NMDA antagonists are analgesic, but the extent of these favorable effects has yet to be defined and clinical utility has been limited by the lack of adequate formulations and toxicity. These drugs usually are considered for very refractory cases.
Topical analgesics are less likely than systemic analgesics to produce side effects and should be considered in a variety of painful disorders. A lidocaine impregnated patch is approved in the United States for treatment of postherpetic neuralgia and, like local anesthetic creams, can be used for neuropathic pain of diverse types. A eutectic mixture of lidocaine and prilocaine penetrates the epidermis and can produce dense cutaneous anesthesia. Topical capsaicin continues to be tried for both neuropathic and musculoskeletal pains, notwithstanding mixed results in clinical trials. Topical NSAIDs may have analgesic effects in arthritic and musculoskeletal pains.
Numerous compounds have been studied in acute musculoskeletal pain syndromes, such as acute low back pain, and have been found to be analgesic. These drugs are centrally-acting analgesics; their analgesic mode of action is unknown. They do not relax skeletal muscle in the clinical setting.
For more information, please see Myofascial Pain.
A large number of adjuvant analgesics are used in the prophylaxis of frequent vascular headache or in the management of chronic daily headache syndrome. In addition to the NSAIDs and opioids, beta blockers (eg, propranolol), anticonvulsants (eg, valproate, gabapentin), calcium channel blockers (eg, verapamil), alpha-2 adrenergic agonists (eg, tizanidine), antidepressants (eg, amitriptyline), vasoactive drugs (isometheptene) and angiotensin-converting-enzyme inhibitors (eg, lisinopril) may be tried.
For more information, please see Headache.
Adjuvant analgesics may be extremely useful in the management of some cancer pain syndromes. The multipurpose drugs and the drugs used for neuropathic pain often are used. Osteoclast inhibitors, including the bisphosphonates and calcitonin, and several radiopharmaceuticals may be helpful for multifocal bone pain. Anticholinergic drugs, such as scopolamine, and the somatostatin analogue, octreotide, are used for pain related to bowel obstruction.
NMDA receptors are important in the central mechanisms of hyperalgesia and chronic pain. Ketamine and oral dextromethorphan are NMDA antagonists that may be used in conjunction with opioids to manage severe neuropathic states. Methadone, a pure opioid agonist, has an intrinsic NMDA antagonistic action, which may add an adjuvant effect for neuropathic pain to the opioid analgesia.
Cholecystokinin (CCK), a major neuropeptide in the CNS, has a role in both endogenous and exogenous pain transmission. CCK-B antagonists, such as proglumide, have been evaluated in clinical trials as adjuncts to opioid therapy in patients with chronic pain. Thus far, results pertaining to efficacy in these trials have been conflicting.
Ultra-low dose opioid antagonists appear to potentiate opioid effects and reverse opioid tolerance. They also are being investigated for clinical use.