Posted by Dr. Gary Mellick on August 01, 1998 at 19:11:10:
In Reply to: Re: Ritalin (methylphenidate) for the Treatment of Cluster Headaches posted by Hampton on August 01, 1998 at 14:06:55:
Dear Hampton:
You brought up some important questions. I don't think we know how Ritalin works but here are some studies by a number of very capable research doctors that I recently compiled.
Warning - Some Very Technical Jargon Follows.
Methylphenidate hydrochloride (Ritalin, MPH) is methyl alpha-phenyl-2-piperidineacetate hydrochloride a mild central nervous system (CNS) stimulant. Ritalin is available as tablets of 5, 10, and 20 mg for oral administration. Ritalin-SR is available as sustained-release tablets of 20 mg for oral administration. The mode of action is not completely understood but MPH presumably activates the brain stem arousal system and cortex to produce its stimulant effect.
Kuczenski and Geyer, et al. showed that the primary effect of MPH on the CNS is to amplify catecholaminergic transmission, but this drug also alters serotoninergic function in the brain stem.
Experiments by Cantello et al, using beta-adrenergic and serotoninergic blockers showed that both the norepinephrine and serotonin systems were involved in the genesis of the methylphenidate-mediated analgesia. Nociceptive neurons in the dorsal horn are potently inhibited by a descending projection from the serotoninergic nucleus raphe magnum in the brain stem and increased transmission by descending norepinephrine neurons capably inhibit the transmission of sensory stimuli to dorsal horn cells.
Quantitative autoradiographic deoxyglucose brain imaging has been very useful for showing how MPH alters local cerebral glucose utilization (LCGU) in rats. Porrino et al. examined rates and distribution of LCGU in 31 cerebral structures and observed that different areas were affected by different amounts of MPH. At the lowest doses administered (1.25 mg/kg), significant increases in glucose metabolism were seen only in the nucleus accumbens, olfactory tubercle, mediodorsal nucleus of the thalamus, the substantia nigra pars reticulata, and lateral frontal granular cortex. When the dose was increased to 2.5 mg/kg, the extrapyramidal system, specifically the globus pallidus, entopendoncular nucleus, and the subthalamic nucleus were significantly affected as well as the compacta and reticulata portions of the substantia nigra. In the limbic forebrain, the nucleus accumbens and the olfactory tubercle showed significant changes.
Various investigations of the role of nucleus accumbens in processing of nociceptive information have shown that microinjection of morphine into the nucleus accumbens produces antinociception ("antinociception" means it blocks pain!). The nucleus accumbens contains opioid receptors and is immunoreactive for both met-enkephalin and beta-endorphin [natural opiates that make you feel good after a you win the 6K race].
Furthermore, Hun and colleagues have proposed the existence of a “mesolimbic loop of analgesia” in which the opioid circuitry in nucleus accumbens plays an important role. Spinal neurons which carry nociceptive (i.e.,pain) information have been shown to project directly to nucleus accumbens and other limbic structures. [The "limbic system" is the brain center of our emotions.]
Gear and Levine have shown that microinjection of naloxone methiodide [naloxone blocks pain relief by opiates] into nucleus accumbens antagonized antinociception actions of intrathecal opioids or local anesthetics.
WHAT COULD ALL THIS MEAN?
1. Ritalin may be doing its headache relieving business somewhere in the brain. My bet is that it could be working at the NUCLEUS ACCUMBENS where a lot of natural opiates hangout. Blocking those opiates would probably block the pain relieving effect of Ritalin.
2. Also, if I am not mistaken, NUCLEUS ACCUMBENS is involved in cocaine and cigarette addiction. I believe these drugs influence the amount of dopamine in our brain! Someone please correct me if I'm wrong. Hampton you are probably right! It might work modulating dopamine!
3. Scientific research is needed to help us better understand how Ritalin relieves cluster headache pain. If any academic centers are interested, cluster headache patients would be very appreciative of any help that you can provide.
All opinions are welcomed.
Dr. Gary Mellick