Symptoms and management of

Neurotrans
mitter

Norepinephrin
e (NE)

Acetylcholine
(Ach)

Substance P

Control
Center

Locus
Coeruleus

Locus
Coeruleus

Periaquedu
ctal Gray

Symptoms

Non-Opioid
Management

Lofexidine
Clonidine

Agitation
Anxiety
Insomnia
Sweating
Piloerection
Diarrhea
Abdominal
cramps
Mydriasis

Lacrimation
Rhinorrhea
Nausea
Emesis

Clonidine
Lofexidine

Abdominal
cramps
Generalized
pain

NSAIDs
Curcumin
Clonidine
Gabapentin

opiates withdrawal
Introduction:
Opioid-withdrawal symptoms result from acute stopping of opioids. They are the following:
agitation, anxiety, insomnia, myalgias, rhinorrhea, diaphoresis, yawning, nausea, emesis,
lacrimation, mydriasis, and piloerection. They are a major reason that drives the opioiddependent patient to relapse. Therefore, alleviating those symptoms encourages the patient
to stop using substance.
This table above groups the symptoms according to the neurotransmitter responsible, and
highlights the drug used to manage them. In addition, we will discuss clonidine and its
potential analgesic effect mainly as adjunct, as well as, Gabapentin, as analgesic, that can be
used to decrease generalized pain.
Clonidine:
Clonidine is an 2 adrenergic receptor agonist. Once conceived as a nasal decongestant, it is
considered today a standard of therapy in todays management of opiates withdrawal. These

agonists owe their widespread use to their symptomatic management of withdrawal

symptoms (well be focusing specifically on the possible analgesic effect they can play).
At the chemical level, the 2 receptors are subdivided into 3 subtypes: 2A, 2B and 2C. All
these subtypes have equal affinity to epinephrine/norepinephrine but differ in their affinity to
exogenous 2 agonists/antagonists.
These molecules have a central mode of action and a peripheral one.
Centrally, the 2 agonists act on the 2A & 2C receptors of the locus ceruleus causing a
sympatholytic response seen as sedation, analgesia and euphoria (thus relieving
restlessness, hyperalgesia and anxiety due to withdrawal).
Peripherally, clonidine was found to prolong the hyperpolarization phase in C fibers of the
vagus nerve, thus increasing the neurons threshold and blocking conduction.
An unwanted peripheral site of action of clonidine are the 2B receptors on vascular smooth
muscle cells of vasculature, explaining the hypotension side-effect associated with clonidine
therapy.
Regardless their subtypes, all 2 receptors share a common biochemical pathway once
activated: these are inhibitory G-protein coupled receptors (GPCRs): Once activated, their
coupled Gi G-protein inhibits adenylyl cyclase, reducing cAMP and ultimately causing a
hyperpolarization, making the involved neuron much less likely to fire (applies for both locus
coeruleus and C fibers).
Clonidine is currently one of the most studied molecules for its antinociceptive potentials.
Although no study was able to prove clonidine to be as an analgesic on its own, multiple
studies proved the compound to have synergistic effect when added to already-known
analgesics, mainly NSAIDs. Using the acetic acid writhing test, the antinociceptive activity of
[clonidine + diclofenac] showed supra-additivity in comparison to diclofenac alone. Should
these experimental findings become daily clinical practice, one would expect a decrease in
the required dose of NSAIDs used for management of withdrawal pain, along with their
associated side-effects.

Gabapentin:
Gabapentin is a GABA analogue used to treat epilepsy, pain relief, and neuropathic pain.
GABA receptors found the locus coeruleus in the pons, where exert an inhibitory action,
preventing the release of adrenergic neurotransmitters, substance P, and others. In a study
done by Behnam et al (2012), Gabapentin was shown to be an effective adjunct in
decreasing opioid-induced pain hyperalgesia.
Dose: 1600 mg/d (Salehi et al, 2011)

References
Tryba, M., & Gehling, M. (2002). Clonidine - a potent analgesic adjuvant. Current
Opinion In Anaesthesiology, 15(5), 511-517.
Behnam, B., Saghafi, N., & Ghorbani, R. (2012). A Randomized Double-Blind Pilot Trial
of Gabapentin versus Placebo to Relieve Iranian Crack-Related Withdrawal Pain. J
Addict Res Ther, 03(02).
Salehi, M., Kheirabadi, G., Maracy, M., & Ranjkesh, M. (2011). Importance of
Gabapentin Dose in Treatment of Opioid Withdrawal. Journal Of Clinical
Psychopharmacology, 31(5), 593-596.
Giovannitti, J., Thoms, S., & Crawford, J. (2015). Alpha-2 Adrenergic Receptor
Agonists: A Review of Current Clinical Applications. Anesthesia Progress, 62(1), 31-38.
Motaghinejad, M., Bangash, M., Hosseini, P., Kariman, S., Motaghinejad, O. (2015).
Attenuation of Morphine Withdrawal Syndrome by Various Dosages of Curcumin in
Comparison with Clonidine in Mouse: Possible Mechanism. Iran J Med Sci, 40(2), 125132.

Motaghinejad, M., Motevalian, M., Asadi-Ghalehni, M., & Motaghinejad, O. (2014). Attenuation
of Morphine Withdrawal Signs, Blood Cortisol and Glucose Level with Forced Exercise in
Comparison with Clonidine. Advanced Biomedical Research, 3, 171