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ilovemybrownies t1_jef15rw wrote

Paradoxically, a small percentage of people who regularly use opioids develop Opioid Induced Hyperalgesia (OIH), which means they basically become sensitized to their own pain.

The current theory about the mechanism is that certain parts of the major pain pathways in your nervous system gain a unique tolerance to the drug's pain relief effects. I'm probably oversimplifying, but it's a real phenomenon and not very well understood.

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svenx t1_jefg3rf wrote

Narcan (Naloxone) blocks endorphin receptors, preventing endorphins (your body's natural pain killer - "endogenous morphine") from doing its job. So while it doesn't directly increase pain, it keeps your body from taking its normal steps to *reduce* that pain, leading to greater overall pain perception.

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ilovemybrownies t1_jefu3on wrote

Replying to Iron_Garuda (#2,542,448)

Thankfully if you stop using long enough it does seem to go away for many people. Some studies suggest it's reversible in the sense that your pain receptors may "reset" their tolerance after roughly 5-6 months of abstinence from the drug. Sometimes doctors have success just rotating opioids in their patient's med schedule and using other pain meds in-between.

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derconsi t1_jefv5wv wrote

Got a bit of knowledge in that department, not enough for credibility tho so Im just sharing my thoughts (in a foreign language, bare with me)

the Sedatives and Analgetics I am Aware of essentially block or slow down the pathway between nerves.

As the Nervous system (divided in two areas: Central NS, the part within your spine and your brain and peripheral NS, all other nerves) uses two one lane streets to work each area (one leading to eg your finger from your brain (motoric) and one the other way around (sensoric) uses transmitters to work.

one could for example try toincrease the production, storage capacity or contact gates of those. That might increase the flat value of sent impulses we interpret as eg pain.

I have to state however that our body has keyholes to those keys all over its body and therefore reacts in most parts of the body to most transmitting agents

(EG adrenaline works the do called "Adrenoceptors" Devided in Alpha1, Alpha2, Beta1 and Beta2 (there seems to be a third pairing Gamma, but as far as I know we havent really understood that one yet). Those are all over our body, so if you inhale Adrenaline to treat eg an anaphylactic shock your lungs will experience the effects first and foremost, but all receptors in your body will take part)

without being capable to explicitly only target the sensoric part of the nervous system the brain would experience an overflow of information, comming from every single nervous cell in our body exposed to the transmitter, wich would probably enforce a reaction similar to an epileptic episode.

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TheMightyAndy t1_jeg427b wrote

The closest answer would be cytokines. These are proteins secreted by the immune system and basically cause inflammation. Some of these cytokines lower the threshold that pain neurons will start to fire at. This is why touching a part of the body that has been hurt is suddenly painful, where applying the same amount of pressure when the body is healthy would not produce the same response.

There's really not a a lot of indications to make these cytokines into drugs, but one, TNF alpha, has been made into a drug to help ramp up the immune system to fight cancer and has "pain" as a side effect. Most non opiate analgesic's block cytokines in one way or another which is how we get pain relief.

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barbzilla1 t1_jeg5ch0 wrote

Replying to ilovemybrownies (#2,533,852)

That's primarily because opiates themselves have very weak analgesic properties. This is why most prescription opiates come with acetaminophen or APAP, as it is one of the most effective analgesics. What the opiates do however, is dump a ton of dopamine on your neurotransmitters causing you to care less about the pain that you were already in. For some reason after perceiving less pain you'll actually start to feel less pain too, and I don't just mean on the short term there is an actual correlation between accepting the pain and lessening the pain

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valleyofdawn t1_jeg6po1 wrote

Acting at the local level there are several naturally-produced molecules the potentiate pain. These include prostaglandin, histamine, and leukotriens. With regard to pain thay generally work by lowering the threshold of pain receptors.

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Vergilx217 t1_jeg92nw wrote

Replying to barbzilla1 (#2,546,548)

...this isn't very correct

Opioids are certainly considered very potent analgesics because of their interactions with the μ, κ, and δ receptors. These generally work through inducing secondary messengers like cAMP to block calcium channels and activate potassium channels, which usually makes it much more difficult for pain sensing neurons to transmit signals. The underlying pathology of addiction is related to dopamine release in the addiction centers like the VTA, but that's certainly different from how pain is actually blocked.

Tylenol is also not a particularly strong analgesic by any stretch, but it works by inhibiting inflammatory pathways. It's often given in conjunction with opioids because it can reduce swelling and discomfort that isn't strictly pain.

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barbzilla1 t1_jeglpd2 wrote

Replying to International_Bet_91 (#2,549,008)

When they are speaking of pain meds here they are testing responsiveness to said pain using the hotplate test with mice. While it has an analgesic property as it brings relief, it is not lessening nerve signals as the topic was about. I realize I'm using layman's terminology, but there are many plants with much better allergies and effects as far as reducing nerve signal. Such as Tylenol and aspirin, so honestly the gold standard is cone snail toxin but most people are prescribed either gabapentin or Lyrica.

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LibertyPrimeIsASage t1_jegv36l wrote

Replying to svenx (#2,538,624)

Really? I took a training course on giving narcan. They said that if someone is not currently on/addicted to opioids, it should have no perceivable effect on them, so if you have suspicion someone ODed and is unresponsive, give it to them, as worst case scenario it does nothing. I now worth it could make a shock case worse. Obviously this is a niche scenario, but I wonder if that's true.

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dougal1084 t1_jegvt3q wrote

Interestingly treatments which cause activation of pain fibres can actually improve pain in some situations. Capsaicin (the spice compound in chillies) can be used as a topical treatment. It causes temporary activation of pain fibres followed by a more prolonged desensitisation which improves pain symptoms in neuropathic conditions such as post-herpetic neuralgia.

Capsaicin has actual physiological effects on pain receptors, but there is also what is called “gate control theory” which is the principle that when your pain receptors are activated, addition of a non-painful stimulus can overwhelm a painful stimulus and reduce pain- it’s why when you bang your knee you rub it and the pain reduces.

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barbzilla1 t1_jeh2h6l wrote

Replying to AAA515 (#2,556,481)

They set the temperature of a scientific hotplate to the level painful but not physically damaging to lab mice, then administer a combo of whatever drug they are testing and a control/placebo to various mice, they then place said mice in said hotplate and time the pain reaction. The mice usually get used for between a week and a month then are either dissected or disposed of.

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Mr_Whispers t1_jeh38rg wrote

Great question OP! I have a PhD in this topic.

TLDR:

  • Drugs such as chemotherapeutic agents that damage the nervous system can enhance pain
  • The term to describe this enhancement is hyperalgesia
  • The processes that cause it are peripheral sensitisation and central sensitisation
  • LTP, or an increase in ion-channel expression at the neuronal synapse, is one of the many mechanisms involved
  • In the case of LTP, the main neurotransmitter is glutamate

Analgesics are drugs that work by reducing pain, and the opposite of this would be drugs that increase pain. The term used to describe an increased pain response is hyperalgesia.

An example of a condition that can lead to increased pain is chemotherapy-induced peripheral neuropathy (CIPN), which is caused by chemotherapeutic agents that damage the nervous system. This damage can result in peripheral sensitisation, through hyperalgesia and ectopic firing. Peripheral sensitisation occurs when the threshold for activation of high-threshold pain receptors is lowered, and their responsiveness is enhanced (hyperexcitability) when they are exposed to inflammatory mediators and damaged tissues. This can lead to central sensitisation as well, but that's a more complicated process [1].

Long-term potentiation (LTP) is one mechanism that can lead to sensitisation through increasing ion channel expression at the synapse. It occurs when the connection between neurons is strengthened due to increased firing frequency between them. Some studies have shown that ketamine, which is an NMDA antagonist that inhibits LTP, can have analgesic effects in cases of peripheral sensitisation [2]. This shows that LTP is one of the mechanisms involved in sensitisation.

P.S.

There are also surgical methods to enhance the pain response which we do in research to model disease. One example is chronic constriction of the infraorbital nerve (CCI-ION) to model trigeminal neuralgia.

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