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They approach the following topics related to the neurobiology of drug addiction.

• Methamphetamine actions on dopamine vesicles.
• LSD action on serotonin receptors.
• Heroin effects on opioid receptors .
• How marijuana interacts with the cannabinoid system and its receptors.
• Activation of the GABA-A ionotropic receptor by alcohol.
• Cocaine action on dopamine reuptake.

This blog has a related post that explains nicotine addiction mechanism through a 3-D video animation.

• Pain management (opioids, nsaids)
• Nausea/Vomiting
• Insomnia
• Anxiety
• Agitation
• Constipation
• Heartburn
• Pruritus
• A couple of more urgent issues
• Electrolytes

How to survive your first night on call. By Matthew Deneke, MD. University of Arkansas for Medical Sciences

Download PPT file

Lecture outline:

• FDA-approved drugs for the treatment of neuropathic pain.
• Pregabalin (EMEA did not approve it for fibromyalgia).
• Duloxetine (read about its mechanism of action in pain).
• Lidocaine patch 5% (FDA warned about its potential side effects).
• Gabapentin.
• Carbamazepine.
• Principles of opiod therapy (see related PowerPoint presentations on opioids).
• Mu opioid receptor polymorphisms.
• Epidural steroid injections rationale, safety and complications.
• Celiac plexus block.
• Spinal drug delivery.
• Neurostimulation delivery.

Lecture: An update on pharmacologic and non-pharmacologic management of neuropathic and cancer pain

• Neuropathic pain.
• Epilepsy in patients who have partial seizures that cannot be controlled with their current treatment.
• Generalized anxiety disorder.

In June 21, 2007; the US Food and Drug Administration approved Lyrica as the first drug for the treatment of fibromyalgia, a year later duloxetine (Cymbalta) became the second.

On 23 April 2009, the European Committee for Medicinal Products for Human Use (CHMP) adopted a negative opinion, recommending the refusal of an extension of indication that would include fibromyalgia treatment as a new indication for Lyrica.

Pfizer requested a re-examination of the opinion. After considering the grounds for this request,
the CHMP re-examined the initial opinion, and confirmed the refusal of the marketing authorisation
on 23 July 2009.

The CHMP was concerned that the benefits of Lyrica in fibromyalgia had not been shown in either the short or the long term. There were no consistent or relevant reductions in pain or other symptoms in the short-term studies, and the maintenance of Lyrica’s effect was not shown in the longer study. The Committee was also concerned that the safety and effectiveness of Lyrica had not been shown in patients from the EU.

Bottom line:

EMEA didn’t approve an extension of indication for Lyrica to include the treatment of fibromyalgia.

Other approved indications (neuropathic pain, generalized anxiety disorder, epilepsy) for Lyrica remain with no changes.

Andrew Moore, from the Nuffield Department of Anaesthetics at the University of Oxford, discusses the available evidence on the use of rubefacients for acute and chronic pain.

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Further reading on rubefacients

Mason L, Moore RA, Edwards JE, McQuay HJ, Derry S, Wiffen PJ. Systematic review of efficacy of topical rubefacients containing salicylates for the treatment of acute and chronic pain. BMJ 2004; 328(7446):995.

European CHMP issues positive opinion on Qutenza® (capsaicin) patch for peripheral neuropathic pain in non-diabetic patients. National electronic Library for Medicines.

Longterm efficacy of topical nonsteroidal antiinflammatory drugs in knee osteoarthritis: metaanalysis of randomized placebo controlled clinical trials. National electronic Library for Medicines.

Prostaglandins & NSAIDs. By Cheryl Tajon and Walter M. Holleran, PharmD. UCSF School of Medicine

Dr. Holleran explores some important biochemical and physiological aspects related to the pharmacology of inflammation.

Outline:

• Formation of Eicosanoids derived from fatty acids.Cyclooxygenase (COX) mechanism.
• Different prostaglandin series (PG1, PG2, PG3).
• Thromboxanes and leukotrienes:  synthesis and physiology.
• Molecular target for NSAIDs. Aryl Propionic Acids, Indole Acids, enol acids.
• NSAIDs that produce analgesia without anti-inflammation.
• 5-Lipoxygenase inhibitors: zileuton. Leukotriene receptor antagonists: montelukast, zafirlukast.
• Histamine and anti-histamines.
• Novel anti-inflammatory approaches.

Download PPT

Non-steroidal Anti-inflammatory Drugs. By Dr Alex Dodoo Ph.D

Dr. Dodoo presentation highlights CSM advise on selective COX-2 inhibitors, among other NSAIDs aspects such as:

• Indications
• Mechanism(s) of Action
• Non-specific Cox or Cox-2
• Side-effects
• Selection

Download PPT

NSAIDs (non steroidal anti-inflammatory drugs). By Theresa C. Peterson, PhD

Dr. Peterson, from the Department of Pharmacology at Dalhousie University, shares an integration between the pharmacology of inflammatory response, NSAIDs and other related drugs (allopurinol, glucocorticoids, etc).

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Gastroprotective Strategies among NSAID users. By Anne-Pascale Bartleman, M.D.

More centered in clinical practice, Dr. Bartleman gives tips on how to protect NSAIDs users from gastrointestinal side effects by reviewing some common gastroprotective medications.

Outline:

• How Common are Side Effects?
• Prevention: use of Misoprostol, Proton Pump Inhibitors, Cox-2 Inhibitor, H2 Receptor Antagonists, sucralfate.
• Pros and cons of celecoxib.
• Risk Factors for GI complications.
• How to Stratify Risk?
• Clinical cases.

Download PPT

As a result of this, the US Food and Drug administration has started a campaign to raise awareness about the potential risks of using methadone as a chronic pain medication. In a recent video, the agency lists a number of steps elaborated by the Institute for Safe Medication Practices to help preventing an overdose when using methadone as chronic pain treatment.

• When prescribing methadone for pain, avoid concomitant use of other narcotics, benzodiazepines, and sedatives, because these significantly increase the risk of an adverse event. Prescribe oral liquid doses of methadone in mg, never in mL alone, since several concentrations exist. Include the indication for use when prescribing methadone, to avoid confusion with methylphenidate. Specify the exact time(s) for administration. If the daily dose is taken in the evening one day and then in the morning the next day, this could lead to an overdose.
•  When dispensing methadone, use commercially available methadone solutions to prevent compounding errors. Stock only one concentration of oral liquid methadone in the pharmacy, if possible. Accept orders for methadone only when the dose is prescribed in mg. Label all unit-doses with the exact dose, including strength and total volume if it is a liquid, along with the date and time for administration.
•  When administering methadone, adhere to standard medication administration times. If a dose is missed, check with the physician before administering it later than originally scheduled. Make sure a pharmacist has reviewed the order before giving the medication to the patient.
•  Remind patients to take methadone exactly as prescribed. Instruct them not to start or stop taking any other medications or dietary supplements without talking to their prescriber, because methadone interacts with many other drugs.
•  Instruct methadone patients to seek medical attention if they experience symptoms of overdose, such as slow or shallow breathing and extreme sleepiness, or symptoms of arrhythmia.

In a related document, Pain-Topics.org gives a practitioner’s guide to the dosing of oral methadone.

Download Oral Methadone Dosing for Chronic Pain (PDF)

Local anesthetics side effects are covered in the March 2009 edition of FDA’s Patient Safety News. The agency’s concern is that after a study published in the the journal Radiology in which the authors suggest the use of topical anesthetics to reduce disconfort during mammography, more and more women will start using them without being warned about side effects such as: cardiac arrythmias, seizures, respiratory depression, coma and even death.

Further information:

Premedication to Reduce Discomfort during Screening Mammography. Radiology, July 2008

Prophylactic drugs overview

The image below reviews the different drug classes used in migraine prophylaxis and acute treatment.

Beta-adrenergic blockers

Propanolol (Inderal, Avlocardyl and others) is the most widely used beta-blocker for migraine prevention, several mechanisms of action are responsible for its effectiveness as a preventive medication:

• It inhibits norepinephrine release through alpha-2 agonism, thus reducing central catecholaminergic activity.
• It antagonizes 5-HT_1A and 5-HT_2Breceptors, reducing neuronal excitability.
• It inhibits nitric oxide production by blocking inducible nitric oxide synthase, through alpha₂-agonist action. Nitric oxide is believed to be the common final pathway for vasodilation in migraine.
• It inhibits excitatory glutamate receptors, decreasing neuronal activity.
• It has membrane-stabilizing properties.

Propanolol dosage for migraine prophylaxis is 80 to 240 mg per day, in three or four divided doses. The usual dose is around 160 mg/d.

Timolol (Betimol)is the other beta-blocker that has been approved by the FDA for the prevention of this clinical condition. The recommended Timolol dose for migraine prophylaxis is 10 to 15 mg twice per day.

All drugs from this class can produce central nervous system adverse effects, such as fatigue, sleep disorders, and depression. Another common side effect is decreased exercise tolerance. Less common are orthostatic hypotension, significant bradycardia, and impotence.

Contraindications to the use of nonselective beta blockers include: congestive heart failure, asthma, and insulin-dependent diabetes.

Calcium channel blockers

Clinical trials have shown that Flunarizine (Sibelium) is an effective prophylactic medication for reducing the frequency of migraine episodes. This drug is not available in the US, its use is common in some European countries and in South America.

Some studies show that flunarizine is as effective as propanolol in reducing severity and frequency of the attacks.

The recommended flunarizine dose in this setting is of 10 mg/d. The most important adverse effect of flunarizine use is weight gain, which limits patient compliance, specially in women.

Evidence does not support the use of other calcium channel blockers. Nimodipine failed to demonstrate any effects in clinical trials, while there is no convincing evidence of the effect of verapamil.

Tricyclic antidepressants

The use of antidepressants for the prevention of migraine episodes has not been approved by the U.S. Food and Drug Administration. However, its off-label use is common and has proved to be effective in the case of amitryptilne.

Amitriptyline (Elavil, Tryptanol and others )is a first-line agent for migraine prophylaxis and is the only TCA with consistent evidence supporting its effectiveness for this use. The dose range for amitriptyline in migraine prevention is 25 to 100 mg.

Side effects are related to TCAs blockade of cholinergic and histamine receptors (read more). These include dry mouth,  tachycardia, constipation, dizziness, mental confusion,  blurred vision, and urinary retention.

Other classes of antidepressants have been considered for migraine prophylaxis, such as SSRI and MAO inhibitors. There is poor evidence for SSRIs use and there are no conclusive randomized controlled trials about the use of MAO inhibitors.

Anticonvulsants

A 2005 Cochrane review supports the use of antiepileptic drugs to reduce headache frequency in patients with migraine. According to that review, valproic acid and divalproex have the strongest evidence to support their use for this indication.

Valproate may raise inhibitory tone in the hyper-excitable migraine brain via GABA. The usual effective dose of divalproex sodium is 500 to 1000 mg/d of the extended release formulation.

Since valproate is a severe teratogenic drug, it should not be used as a first line preventive medication in women of child-bearing age.

Topiramate (Topamax) has a variety of actions that may prevent migraine, including increasing inhibitory GABA activity, blocking calcium channels, and inhibiting carbonic anhydrase.

Topiramate is well tolerated when started at a low dose, usually 15 or 25 mg, and increased weekly up to 100 mg, which is the recommended dose. Topiramate is associated with weight loss in around 4% of treated patients.

Gabapentin (Neurontin) recommended dose is between 900 and 3600 mg qd. Just as pregabalin, it acts by modulating glutamate and GABA function, as well as regulating intracellular calcium influx. Among the most common adverse effects are dizziness and sedation.

Clinical guidelines for migraine prophylaxis

Evidence-based  guidelines  for migraine headache  in  the  primary  care  setting: pharmacological management  for prevention of migraine. American Academy of Neurology.  Download PDF

Pharmacologic management  of  acute  attacks  of migraine and prevention of migraine headache. Ann Intern Med 2002;137:840-9. Download PDF

Your opinion and experience matters

Please take a minute to share with your colleagues some of your experience on the use of the medication discussed above. Your thoughts are of great interest to the Pharmacology Corner community, leave your comments on the form below the post.

References

Chronicle E, Mulleners W. Anticonvulsant drugs for migraine prophylaxis. Cochrane Database Syst Rev 2004;(4):CD003226.

Modi, S, , Lowder, D.Medications for Migraine Prophylaxis. Am  Fam  Physician. 2006;73:72-8, 79-80.

Fauci, Anthony S., Braunwald, Eugene, Kasper,Dennis L. “Harrison’s Principles of Internal Medicine”, 17 edition. Mc Graw Hill: 2008.

Diener HC, Matias-Guiu J. Efficacy and tolerability in migraine prophylaxis of flunarizine in reduced doses: a comparison with propranolol 160 mg daily. Cephalalgia. 2002 Apr;22(3):209-21.

Bordini CA, Arruda MA. Propranolol vs flunarizine vs flunarizine plus propranolol in migraine without aura prophylaxis. A double-blind trial. Arq Neuropsiquiatr. 1997 Sep;55(3B):536-41