Analgesic adjuvant

Short description: Medication used for other purposes that additionally has analgesic effects

An analgesic adjuvant is a medication that is typically used for indications other than pain control but provides control of pain (analgesia) in some painful diseases. This is often part of multimodal analgesia, where one of the intentions is to minimize the need for opioids.[1][2][3]

## Contents

* 1 Rationale
* 2 Types of Analgesic Adjuvants
* 2.1 Anticonvulsants
* 2.2 Antidepressants
* 2.3 Muscle relaxants
* 2.4 Alpha-2 Adrenergic Agonists
* 2.5 Other Pharmacologic Compounds
* 3 References
* 4 External links

## Rationale

Multimodal analgesia refers to the use of multiple classes of medications in order to treat pain from different molecular mechanisms at once. Prolonged use of higher doses of opioids is associated with increased risk of tolerance and opioid use disorder, so there is a growing trend in the use of multimodal analgesia to treat pain.[4][5][6]

## Types of Analgesic Adjuvants

### Anticonvulsants

Anticonvulsants work through blockade of sodium and calcium ion channels to reduce glutamate (excitatory neurotransmitter) release.[7] Nociceptor hyper-excitability, due to damage to pain-transmitting neurons, results in chronic neuropathic pain. Common anticonvulsants used to treat neuropathic are gabapentinoids (calcium channel blockers) and carbamazapine (sodium channel blocker).[8] There is some evidence that anticonvulsants may also help with inflammatory pain through reduction of nociceptor hyper-excitability originally due to damage to surrounding tissue.[9]

* Examples:
* Gabapentin
* Pregabalin
* Carbamazepine: FDA-approved for trigeminal neuralgia[10]

### Antidepressants

Antidepressants act (as treatment for both depression and pain) by modulating serotonin and norepinephrine neurotransmitter metabolism. Descending serotonin pathways in the spinal cord are implicated in modulation of pain perception, especially in chronic pain.[11] Common agents used are serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs). Duloxetine, venlafaxine, and amitriptyline are all FDA-approved for chronic musculoskeletal pain, peripheral neuropathy, and fibromyalgia).[12][13][14]

* Examples:
* Duloxetine
* Venlafaxine
* Amitriptyline

### Muscle relaxants

Over-excitation of skeletal muscle can result in spasticity (increased muscle tone) and/or muscle spasms (involuntary muscle contractions) which may contribute to pain.[15] There are several different types of muscle relaxants used for pain with different mechanisms of action. Muscle relaxants often have sedating effect that contributes to analgesia and improved relaxation. Experts disagree over whether muscle relaxants are useful for acute musculoskeletal pain.[16]

* Examples:
* Cyclobenzaprine
* Methocarbamol
* Tizanidine
* Baclofen
* Carisoprodol: also active centrally and reduces perception of pain[15]
* Diazepam

### Alpha-2 Adrenergic Agonists

Alpha-2 adrenergic agonists such as clonidine are traditionally used to treat hypertension via inhibition of norepinephrine release.[17] Central alpha-2 adrenergic activation in the locus ceruleus and spinal cord induce sedation and pain modulation respectively.[17] Clonidine has been shown to have some efficacy when treating both acute and chronic pain.[18]

* Examples:
* Clonidine
* Tizanidine: also considered a muscle relaxant

### Other Pharmacologic Compounds

Many other classes of pharmacologic compounds have been found to have analgesic potential in certain situations. Several compounds used as adjunctive analgesics include antihistamines (hydroxyzine, promethazine), cannabinoids, NMDA receptor antagonists (ketamine, memantine), scopolamine, and caffeine.[citation needed]

## References

1. ↑ Portenoy, Russell K. (April 2020). "A Practical Approach to Using Adjuvant Analgesics in Older Adults". Journal of the American Geriatrics Society 68 (4): 691–698. doi:10.1111/jgs.16340. ISSN 1532-5415. PMID 32216151. https://pubmed.ncbi.nlm.nih.gov/32216151/.
2. ↑ Wheeler, Kathleen E.; Grilli, Ryan; Centofanti, John E.; Martin, Janet; Gelinas, Celine; Szumita, Paul M.; Devlin, John W.; Chanques, Gerald et al. (July 2020). "Adjuvant Analgesic Use in the Critically Ill: A Systematic Review and Meta-Analysis" (in en-US). Critical Care Explorations 2 (7): e0157. doi:10.1097/CCE.0000000000000157. PMID 32696016. PMC 7340332. https://journals.lww.com/ccejournal/fulltext/2020/07000/adjuvant_analgesic_use_in_the_critically_ill__a.6.aspx.
3. ↑ Hamburger, J.; Beilin, Y. (2019-11-01). "Systemic adjunct analgesics for cesarean delivery: a narrative review". International Journal of Obstetric Anesthesia 40: 101–118. doi:10.1016/j.ijoa.2019.06.009. ISSN 0959-289X. PMID 31350096. https://www.sciencedirect.com/science/article/pii/S0959289X18303492.
4. ↑ Morgan, Michael M; Christie, MacDonald J (October 2011). "Analysis of opioid efficacy, tolerance, addiction and dependence from cell culture to human" (in en). British Journal of Pharmacology 164 (4): 1322–1334. doi:10.1111/j.1476-5381.2011.01335.x. ISSN 0007-1188. PMID 21434879.
5. ↑ Kaye, AlanDavid; Urman, RichardD; Rappaport, Yury; Siddaiah, Harish; Cornett, ElyseM; Belani, Kumar; Salinas, OrlandoJ; Fox, CharlesJ (2019). "Multimodal analgesia as an essential part of enhanced recovery protocols in the ambulatory settings" (in en). Journal of Anaesthesiology Clinical Pharmacology 35 (5): S40–S45. doi:10.4103/joacp.JOACP_51_18. ISSN 0970-9185. PMID 31142958.
6. ↑ Olmos, Andrea V.; Steen, Sasha; Boscardin, Christy K.; Chang, Joyce M.; Manahan, Genevieve; Little, Anthony R.; Lee, Man-Cheung; Liu, Linda L. (2021-07-01). "Increasing the use of multimodal analgesia during adult surgery in a tertiary academic anaesthesia department" (in en). BMJ Open Quality 10 (3): e001320. doi:10.1136/bmjoq-2020-001320. ISSN 2399-6641. PMID 34281910. PMC 8291327. https://bmjopenquality.bmj.com/content/10/3/e001320.
7. ↑ Kammerer, M.; Rassner, M. P.; Freiman, T. M.; Feuerstein, T. J. (July 2011). "Effects of antiepileptic drugs on GABA release from rat and human neocortical synaptosomes" (in en). Naunyn-Schmiedeberg's Archives of Pharmacology 384 (1): 47–57. doi:10.1007/s00210-011-0636-8. ISSN 0028-1298. PMID 21533993. http://link.springer.com/10.1007/s00210-011-0636-8.
8. ↑ Sidhu, Harpreet S.; Sadhotra, Akshay (2016). "Current Status of the New Antiepileptic Drugs in Chronic Pain". Frontiers in Pharmacology 7: 276. doi:10.3389/fphar.2016.00276. ISSN 1663-9812. PMID 27610084.
9. ↑ Tomić, Maja; Pecikoza, Uroš; Micov, Ana; Vučković, Sonja; Stepanović-Petrović, Radica (2018-12-01). "Antiepileptic drugs as analgesics/adjuvants in inflammatory pain: current preclinical evidence". Pharmacology & Therapeutics 192: 42–64. doi:10.1016/j.pharmthera.2018.06.002. ISSN 0163-7258. PMID 29909236. https://www.sciencedirect.com/science/article/pii/S0163725818301049.
10. ↑ "DailyMed - TEGRETOL- carbamazepine suspension TEGRETOL- carbamazepine tablet TEGRETOL XR- carbamazepine tablet, extended release". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8d409411-aa9f-4f3a-a52c-fbcb0c3ec053.
11. ↑ Chen, Jiatong (Steven); Kandle, Patricia F.; Murray, Ian V.; Fitzgerald, Lauren A.; Sehdev, Jasjit S. (2023), "Physiology, Pain", StatPearls (Treasure Island (FL): StatPearls Publishing), PMID 30969611, http://www.ncbi.nlm.nih.gov/books/NBK539789/, retrieved 2023-11-06
12. ↑ "Cymbalta (duloxetine hydrochloride) capsules". 2010. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022516lbl.pdf.
13. ↑ "EFFEXOR XR® (venlafaxine Extended-Release) Capsules". 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020699s107lbl.pdf.
14. ↑ "Amitriptyline Hydrochloride Tablets, USP". https://www.accessdata.fda.gov/spl/data/0f12f50f-7087-46e7-a2e6-356b4c566c9f/0f12f50f-7087-46e7-a2e6-356b4c566c9f.xml.
15. ↑ 15.0 15.1 Fudin, Jeffrey; Mena, Raouf. "A Review of Skeletal Muscle Relaxants for Pain Management". Practical Pain Management 16 (5). https://www.practicalpainmanagement.com/treatments/pharmacological/non-opioids/review-skeletal-muscle-relaxants-pain-management.
16. ↑ Schoonover, Julie; Rubin, Susan E. (March 2022). "Should Muscle Relaxants Be Used as Adjuvants in Patients With Acute Low Back Pain?" (in en-US). American Family Physician 105 (3): 221. ISSN 1532-0650. PMID 35289585. https://www.aafp.org/pubs/afp/issues/2022/0300/p221.html.
17. ↑ 17.0 17.1 Giovannitti, Joseph A.; Thoms, Sean M.; Crawford, James J. (2015). "Alpha-2 Adrenergic Receptor Agonists: A Review of Current Clinical Applications". Anesthesia Progress 62 (1): 31–38. doi:10.2344/0003-3006-62.1.31. ISSN 0003-3006. PMID 25849473.
18. ↑ Kumar, Anil; Maitra, Souvik; Khanna, Puneet; Baidya, Dalim Kumar (2014). "Clonidine for management of chronic pain: A brief review of the current evidences". Saudi Journal of Anaesthesia 8 (1): 92–96. doi:10.4103/1658-354X.125955. ISSN 1658-354X. PMID 24665248.

## External links

* WHO Guidelines on the Pharmacological Treatment of Persisting Pain in Children with Medical Illnesses, (2012), World Health Organization

* v
* t
* e

Analgesics (N02A, N02B)

Opioids|

| Opiates/opium|

* Codeine# (+paracetamol, +aspirin)
* Morphine# (+naltrexone)
* Opium
* Laudanum
* Paregoric

|

Semisynthetic|

* Acetyldihydrocodeine
* Benzylmorphine
* Buprenorphine (+naloxone)
* Desomorphine
* Diamorphine (heroin)
* Dihydrocodeine (+paracetamol)
* Dihydromorphine
* Ethylmorphine
* Hydrocodone (+paracetamol, +ibuprofen, +aspirin)
* Hydromorphinol
* Hydromorphone
* Nicocodeine
* Nicodicodine
* Nicomorphine
* Oxycodone (+paracetamol, +aspirin, oxycodone/ibuprofen

Synthetic|

* Alfentanil
* Alphaprodine
* Anileridine
* Butorphanol
* Carfentanil
* Dextromoramide
* Dextropropoxyphene
* Dezocine
* Fentanyl# (+fluanisone)
* Ketobemidone
* Levorphanol
* Lofentanil
* Meptazinol
* Methadone#
* Nalbuphine
* NFEPP
* Pentazocine
* Pethidine (meperidine)
* Phenadoxone
* Phenazocine
* Piminodine
* Piritramide
* Propiram
* Remifentanil
* Sufentanil
* Tapentadol
* Tilidine
* Tramadol

Paracetamol-type|

* Acetanilide‡
* Bucetin‡
* Butacetin‡
* Paracetamol (acetaminophen)#
* Parapropamol‡
* Phenacetin‡
* Propacetamol‡

NSAIDs|

| Propionates|

* Fenoprofen
* Flurbiprofen
* Ibuprofen#
* Ketoprofen
* Naproxen
* Oxaprozin

|

Oxicams|

* Meloxicam
* Piroxicam

Acetates|

* Diclofenac
* Indometacin
* Ketorolac
* Nabumetone
* Sulindac
* Tolmetin

COX-2 inhibitors|

* Celecoxib
* Etoricoxib
* Lumiracoxib
* Parecoxib
* Rofecoxib ‡
* Valdecoxib ‡

Fenamates|

* Meclofenamic acid
* Mefenamic acid

Salicylates|

* Aspirin (acetylsalicylic acid)# (+paracetamol/caffeine)
* Benorylate
* Diflunisal
* Ethenzamide
* Magnesium salicylate
* Salicin
* Salicylamide
* Salsalate
* Wintergreen (methyl salicylate)

Pyrazolones|

* Aminophenazone‡
* Ampyrone
* Metamizole (dipyrone)
* Nifenazone
* Phenazone
* Propyphenazone (+paracetamol/caffeine)

Others|

* Glafenine

Cannabinoids|

* Cannabidiol
* Cannabis
* Nabilone
* Nabiximols
* Tetrahydrocannabinol (dronabinol)

Ion channel
modulators|

| Calcium blockers|

* Gabapentin
* Gabapentin enacarbil
* Mirogabalin
* Pregabalin
* Ziconotide

|

Sodium blockers|

* Carbamazepine
* Lacosamide
* Local anesthetics (e.g., cocaine, lidocaine)
* Mexiletine
* Nefopam
* Tricyclic antidepressants (e.g., amitriptyline#)

* Nav1.7/1.8-selective: DSP-2230§
* Funapide§
* PF-05089771§

Potassium openers|

* Flupirtine

Myorelaxants|

* Carisoprodol
* Chlorzoxazone
* Cyclobenzaprine
* Mephenoxalone
* Methocarbamol
* Orphenadrine

Others|

* Analgesic adjuvant
* Analgecine
* Camphor
* Capsaicin
* Clonidine
* Ketamine
* Menthol
* Methoxyflurane
* Nefopam
* Proglumide
* Tricyclic antidepressants (e.g., amitriptyline#)

* #WHO-EM
* ‡Withdrawn from market
* Clinical trials:
* †Phase III
* §Never to phase III

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