Neuropathic and inflammatory pain

Nociception (pain perception) is a critical mechanism of the body self-defence, inducing to discontinue a stimuli potentially deteriorating.
When pain is experienced chronically,often as a consequence of a neural or metabolic dysfunction, as in the case of neuropathic pain (NP), it is fundamental to find agents able to target the pathways producing allodynia (sensation of pain evoked by a stimulus which would not, normally, produce it) and ultimately to eradicate them. [1]
 
It has been estimated that 7-8% of the entire population of Western Countries develops neuropathic pain, which is often caused by other pathologies (cancer, diabetes, Multiple Sclerosis, HIV or stroke, just to mention a few).[2]
Despite the aetiology of the disease is multifarious, it causes the nervous system to be hypersensitised due to prolonged impulses.
 
Neuropathic pain alone is a chronic debilitating disease that affects up to 4 million people just in Europe; given the poor outcome of the medicines currently in use for the management of symptoms, (gabapentin, opioids and tricyclic antidepressant mainly) many studies are focussed on this field of study. [3]

 
Why using cannabinoids?
Phytocannabinoids have been extensively used throughout history for various therapeutic purposes, particularly analgesic. However, the cannabinoid circuitry is relatively young, with only 20 years since its first characterization by the pioneering studies of Raphael Mechoulam, whose discoveries conveyed these chemicals from traditional home remedies to pharmacological investigation. [4]
 
Since the discovery of Cannabinoid receptors pain regulation became one of the main area of study. Compelling evidence has shown that cannabinoids decrease allodynia both thermal and mechanical, proving their role for treating neuropathic pain. [5]
 
Cannabinoids vs opioids
The main mediator of the antinociceptive effect is thought to
be the cannabinoid CB1 receptor. The benefit of targeting directly CB1 receptors is endorsed by their anatomical distribution in core pain centers of the brain (Periaqueductal grey-substantia gelatinosa-medulla oblongata-dorsal horn). [6]
 
 CB1 agonists (all the drugs that activate CB1 receptors, such as THC) prevent “wind-up” phenomenon in the dorsal horn (an exaggerated sensitization to pain leading to allodynia and hyperalgesia and hallmark of neuropathic pain). (Hyperalgesia =increased sensation to pain, usually due to damaged pain receptors and nerve terminals)
It is hence crucial to pinpoint that manipulating cannabinoid circuitry is more advantageous than targeting directly opioids for the treatment of neuropathic pain. [6, 7]
 
Moreover, the medicines that activate CB1 receptors maintain their efficacy, at the opposite of morphine, which is less potent over time (so that more doses are needed, and with it, an increase in side effects).
Importantly, the spontaneous discharge (which lead to pain sensation) has been located mainly in primary afferent myelinated A-fibres, which are rich in cannabinoid receptors rather than opioids. [8]
 
The current medications for treating pain are still mainly opioids, but only approximately 50% of the sufferers finds relief with the available cures, thus highlighting how the clinic would greatly benefit from drugs oriented on cannabinoids modulation. [2]

On the ring today...

Opioids are prescribed worldwide to deal with pain.
Only recently Sativex has been approved for treatment of pain in 2 Countries only! If you want to know more click here.
Here are some facts, all the side effects, both very common and rare for both medications.
Remember that researching cannabinoids medications does not necessarly mean using THC-based medications and lots of research is going through in this direction, making cannabinoid-based drugs even safer and non-psychoactive.

 

Side effects	Cannabis	Morphine
		blood pressure chages
		constriction of the pupil of the eye
		irregular heart rate
	increased heart rate	erectile dysfunction
Cardiovascular	redness of the eyes	eye or eyesight problems
	vasodilatation/facial flush	facialflushing
		irregular heart rate
		oedema of the extremities
		palpitations
	aids sleeping	difficult sleeping
Circadian	somnolence	sleepiness
	aids gastrointestinal functions (diarrhea is rare)	biliary problems
Gastrointestinal	anti-emetic, can cause nausea when overdosed	constipation
	eases cramps	gastrointestinal problems
	abdominal pain can occur (rare)	indigestion
		nausea
		vomiting
		stomachpain
		amenorrhoea
Hormonal		decreased libido
		allergic reactions
		anaphylactic reactions
Immunologic	anti-inflamatory	itching
		skin rash or rashes
		worsening of pancreatitis
		urticaria
Muscolar	muscle relaxant	abnormal muscle movement
	unsteadiness	muscle twitching
		confusion
		drowsiness
		headaches
		loss of appetite
		thinking problems
		weakness
	confusion	convulsions
	drowsiness	dysphoria- euphoria
	increased appetite	fainting
	weakness	feeling agitated
Neurologic	euphoria	general feeling of being unwell
	sense of well-being	hallucinations
	depersonalization	mood changes
	hallucination	physical dependence
	paranoid reaction	psychological dependence
		vertigo
		withdrawal symptoms
		bronchospasm
Respiratory	bronchodilator	pulmonary oedema
		respiratory depression
		severe dry mouth
		sweating
Salivation	dry mouth	renal spasms
		urinary retention

List of references:

1. Scadding, J. (2003). Neuropathic Pain.ACNR. 3 (2), 8-14.
2. Mao, J., Price, D.D., Lu, J., Keniston, L., Mayer, D.J. (2000) Two distinctive antinociceptive systems in rats with pathological pain. Neurosci. Lett., 280, 13-16.
3. Selph, S Carson, S Fu, R et al. (2011). Drug Class Review Neuropathic Pain. Available: ncbi.nlm.nih.gov . Last accessed 4/3/13 .
4. British Medical Association (1997) Therapeutic Uses of Cannabis. London, Harwood Academic Publishers
5. Fox, A., Kesingland, A., Gentrym C., McNair, K., Patel, S., Urban, L., James, I. (2001) The role of central and peripheral Cannabinoid 1 receptors in the antihyperalgesic activity of cannabinoids in a model of neuropathic pain. Pain, 92, 91-100.
6. Martin, B.R., Lichtman, A.H. (1998) Cannabinoid transmission and pain perception. Neurobiol.Dis., 5, 447-461.
7. Lichtman, A.H., Martin, B.R. (1991) Spinal and supraspinal components of cannabinoid-induced antinociception. J.Pharmacol. Exp. Ther., 258, 517-523.

Author: Viola Brugnatelli, BSc Neuroscience - Source: Casey McClain at naturegoingsmart.com/