seriously. i’m highly irritated with this supposed moral position that opiates should not be used in pain treatment. (really- where the hell does this opinion even come from?! that’s what opiates DO!) i think people shouldn’t inflict their lack of knowledge upon others. so i’m going to talk a little bit (looking back, i talk about more than just a little bit!) about opiates and how they work in pain transmission mechanisms, so that my readers will be educated if they should ever happen upon such an ignorant assertion based upon no facts and only personal judgment. opiates are very well known effective pain-modulating agents. their known issues with tolerance, dependence, and possible addiction, and their fairly easy availablility on the street give them a general bad name. this can be deserved or not, depending on the application.
let’s start with the opioid receptors.
yes, my astute readers, you have probably noticed i just switched to “opioid” instead of “opiate”- allow me to explain briefly. this is just a terminology issue. opiates are exogenous. opioids are endogenous. that’s all. now let’s continue.
we have three types of opioid receptors. they are the mu, kappa, and delta subtypes. (they are labeled as such because of the pharmacological ligand that was used to identify them, and of course they had to be greek letters, because science loves teh greek letterz.) each subtype has its own endogenous endorphin peptide ligand- beta-endorphin, dynorphin, and enkephalin, respectively. the major opioid target we have for pain is mu, with most of the well known agonists used in pain treatment binding as agonists to mu receptors. kappa receptors do play a role as well, but we have fewer kappa agonists; and since dysphoria is a side effect of kappa activation, it’s a presumably less desirable target. delta receptors produce very mild analgesia, and we have few well-understood agonists for these receptors. regardless, all of the opioid receptors are located postsynaptically to the endogenous opioid-producing neurons, and produce an inhibitory effect upon the postsynaptic cell via G protein coupled mechanisms.
opioid receptors are found throughout the brain. the real bitch about neuropharmacology is that, short of microinjecting something straight into a certain region of the brain (which you can imagine, is not done in general practice in people) you can not target regions of the brain specifically. so if you put an opiate into your brain, you’re affecting all opioid-mediated processes- including the respiratory depression, euphoria, and of course downstream dopaminergic stimulation/reward which can in some cases lead to addictive behavior. these are all things we would rather not mess with, that make the opiates dangerous when played with carelessly. this is why risk and benefit must be weighed, and appropriate medical supervision is required when opiate drugs are used. it’s also why we’re very glad that we have antagonists like naloxone that can save you from an overdose.
next: pain transmission- the ascending and descending pathways
now that we’ve got a basic understanding of the opioid receptors and how they function, we need to know about the pain pathways that they interact with.
there are two general pathways in pain transmission: the signal that goes from your sensory neurons to the spinal cord to your brain, and the feedback from your brain back to your spinal cord. these are the ascending (up to the brain) and descending (down from the brain) pathways. each direction of signal travels through varying channels:
the ascending pathways are comprised of multiple circuits. signal is sent through the spinothalamic tract- as you might guess from the name, this sends information from the level of your spinal cord to your thalamus, where sensory information (and much more!) is processed and sent along to other parts of your brain. this basically sends the signal that an insult to the body has occurred and the sense and location information of pain that accompanies it. some signal is also sent to the periaqueductal grey (PAG) and then to the thalamus through this pathway.
the spinomesencephalic (spinal cord to midbrain) tract sends information to the PAG and superior colliculus. these two regions are less directly involved in the actual sense of pain, and more involved in the modulation of perception and behavior (and emotion) related to pain. the involvement of these regions are probably the reason that pain is highly subjective and individuals have different experiences of pain. the PAG is also involved in the descending pathway, which i will get to briefly. (i know, that’s kind of confusing, right? stick with me here.)
there is also a spinoreticular tract- projecting to the reticular area (an evolutionarily very old part of your brain involved in basic functions, among them pain processing), then along to the thalamus. in another confusing switch, the reticular area may also regulate the descending pain pathway.
the descending pathway, then, takes information from the brain and send it back down to the spinal cord as a feedback mechanism. this is just another homeostatic pathway- the brain gets the signal that pain is present, but that signal can then in turn be dampened by the brain on its way up from the body. (imagine it as if you want to turn down some very loud music. you will still hear it once you turn it down, but you don’t need THAT much signal going into your ears. that is the best analogy i can come up with right now for this negative regulation.) the major descending pathway is from the PAG to the medulla, to the dorsal horn of the spinal cord. the descending pathway modulates the ascending pathways at the spinal cord level. also, i might mention that the PAG is full of opioid receptors. just keep that in mind.
so, let’s recap: ascending pathways send information about pain to the brain, where different brain regions process sensory, emotional and behavioral responses. descending pathways send signal from the brain back to the spinal cord, where modulation (dampening) of the ascending pain signal can occur.
where and how opioids act upon the pain pathways
alright, so now we know about the opioid receptors, and we know about the pain pathways. but what is so special about the location of opioid receptors that makes them so well-poised to modulate pain?
well, to cut to the chase here, opioid receptors in the spinal cord inhibit ascending pain signals. all ascending signals must pass from the sensory neurons, up the spinal cord, to the brain. when you throw an agonist on the mu receptors in the spinal cord- like, say, morphine or hydrocodone- they inhibit neuronal firing (via that inhibitory G protein coupled signaling i mentioned earlier) in the ascending pathway. the signal is not transmitted to the brain!
to make this a double-score for opiates, they stimulate descending pathways- the pathways that dampen pain signal transmission. this is a little more complex- you may be wondering now, since stimulating the opioid receptor is inhibitory, why this action stimulates the descending pathways? this is a little more complex, so i’m going to put that in its own section with its own set of explanations.
mechanism of opioid stimulation of descending pathways
remember that the brain is driven by, most basically, a series of additive binary signals. excitatory transmission leads to neuron firing, but inhibitory transmission makes it less likely that the neuron will fire. the sum of inputs determines the outcome- whether the neuron fires or not. keep this in mind as you read this next part.
the descending pathway is tonically inhibited by GABA in the PAG, recall this is the major inhibitory neurotransmitter in the brain. so under normal conditions, GABA is keeping the key neurons from firing. this is fine, not a problem, it’s the way things normally work. but the cool thing starts here. we have opioid receptors on the GABA neurons- so endogenous opioids and opiate drugs work by inhibiting the inhibition of the pathway. by removing the inhibition, now these pathway neurons are able to fire and the descending pathway can dampen the pain signal coming up to the brain. really, how amazingly brilliant is that?!
so to put it all together
ascending pathways are blocked by opiates. this keeps pain signal from reaching your brain. in addition, opiates indirectly stimulate the descending pathways, which dampen the pain signal on its way up to the brain. this is a double whammy against pain signaling, which is quite effective, as you might imagine.
but leigh, what about side effects? and addiction?
these are big issues. opiates are NOT wonder drugs. people become tolerant to the pain effects pretty rapidly, but tolerance to the respiratory depression effects doesn’t necessarily occur at the same rate. when you become tolerant to the pain relief, you might choose to take increasing doses of the drug to keep that pain relief effect going. however, this can put you dangerously close to respiratory failure. typically, opiate overdose becomes fatal due to respiratory suppression. it’s convenient then, that you never become tolerant to miosis (constricted pupils), because that is a good indicator that you’ve been taking opiates. in the case of overdose, if you’re really lucky and wind up in the ER, this might just get you identified as someone who stopped breathing due to opiate overdose and save your life. then, hopefully you’ve learned your lesson not to fool with the opiates.
the other side effects aren’t a picnic either. itching, insufficient thermoregulation (you can get really hot and sweaty- this is thanks to the opioid receptors in your brainstem), and constipation (due to the opioid receptors that regulate GI muscle motility). not to mention nausea and vomiting.
the biggest concern that people seem to have about these drugs is that you can get addicted to them. this is a legitimate concern, but not everyone who takes an opiate will become an addict.
addiction via the dopaminergic pathway
it turns out that opioid receptors also play a big role in regulating signaling in the dopaminergic system. go figure. remember the receptors are inhibitory. and we just talked about how they can indirectly stimulate a pathway by inhibiting GABA signaling. well, mu receptors are located on GABA neurons that are presynaptic to dopamine neurons! mu agonists then relieve inhibition on dopamine neurons, indirectly driving dopamine firing. that’s how mu agonists drive reward, and that property gives them addiction liability. remember that i mentioned kappa receptors had the side effect of dysphoria? they are located on dopamine neurons, and stimulating them with an agonist decreases dopamine firing. so as you might imagine, kappa agonists don’t have the same addiction liability that mu agonists do.
how to responsibly handle these drugs?
there are plenty of people who take opiates to manage pain. so how do they do it, with all the seeming risks? quite simply, they follow the instructions given by their doctor. when they become tolerant, their doctor should put them on a drug holiday to restore opioid receptor sensitivity and number at the membrane. (i’ve discussed the receptor-mediated mechanisms of tolerance previously if you’d like to catch up on that topic.) there is great responsibility for both doctor and patient to ensure that the drug is working to the benefit of the patient. a prevalent method in pain management clinics is to have a contract that outlines a very specific set of rules the patient must follow to ensure that the drugs are not being misused or redirected. in the case i am familiar with, the patient is evaluated by a psychiatrist prior to initiation of opiate therapy. then, they are subject to randomized drug testing at any time, must bring in their remaining pills for counting at every doctor visit, and must always use the same pharmacy. they are not allowed to obtain pain medications from any other doctor. any violation of these contractual rules leads to revocation of the opiate, and the patient is given drugs to counteract the effects of withdrawal. (this is important, since withdrawal can be very unpleasant indeed. and this is also one of the reasons it is just downright cruel to just randomly, senselessly deny somebody an opiate prescription when they are on long-term opiate pain maintenance.)
yes, opiates are quite effective in pain management. when used properly, they do their job well by hitting both ascending and descending pain pathways. there are risks, but the responsible use of opiates is key and falls on the shoulders of the doctor and the patient. misuse and recreational use have given these drugs a bad name- as our country struggles with this so-called war on drugs, people become increasingly judgmental of people who are taking opiate drugs. this is not necessary. a person managing pain with an opiate is not an addict or a criminal, they are simply using a very effective drug- likely because they’ve tried everything else without success. this does not constitute something that we can make a moral judgment upon. it does constitute the best use of medical knowledge that we have to improve the lives of others, which is what gets a lot of us out of bed in the morning even when work seems a little overwhelming.
and that’s all i have to say about that.