Pharmacological treatment

Pharmacological treatment is an important (but complicated) aspect of multimodal chronic pain management. While it is rarely enough as a stand-alone treatment, it can improve the quality of life of people with chronic pain. The key is finding the balance between effective treatment and acceptable side effects. Unfortunately, most painkillers have a lot of side effects that interfere with the patient's daily life, e.g. tiredness, fatigue, drowsiness, and dizziness. Side effects like these can affect your ability to work or study, your family and social life, as well as your ability to be active and exercise, among other things. When used regularly for a longer period of time, there is an even higher risk of long-term side effects and complications - not to mention the risk of developing tolerance and addiction.

Despite all of this, pharmacological treatment can have a positive effect on a lot of people. It is, however, important to be well-informed about the possible side effects, risks and consequences, and to weigh the pros and cons before making any decisions. The physician who prescribes the medication should ideally be a pain management specialist, or at least have a lot of experience treating people with chronic pain. Regular follow-up appointments are essential in order for the doctor to evaluate your treatment, make necessary changes, and identify early signs of drug addiction, dependence and tolerance.

Each patient's drug therapy should always be individualized and tailored to their particular needs and situation. What works for one person may not suit everyone. That being said, it always helps to be informed and educated about pharmacological treatment in general, which is why I've written this section. On this page, you will find everything from basic principles of pharmacology to specific information about the different kind of drugs that are used to manage chronic pain.

Types of drugs

There are several different types of drugs used to treat chronic pain. The most common ones are paracetamol (also known as acetaminophen), NSAIDs, opioids, antidepressants, and anticonvulsants. They all have different properties and mechanisms of action, so the choice of medicine will depend on the type and cause of your pain. People who have more than one type of pain (e.g. both neuropathic and inflammatory pain) often benefit from a combination of two or more medications that target all components.

Paracetamol/acetaminophen

Paracetamol (also known as acetaminophen in the US) is one of the most common over-the-counter drugs used to treat fever and mild to moderate pain. Although paracetamol isn't powerful enough to treat severe pain on its own, it can relieve at least some of the pain when taken regularly (1 gram, 4 times a day) and is therefore often recommended as a first-line treatment. When used in combination with certain other painkillers, e.g. opioids, it can also enhance their pain relieving effect.

Side effects from paracetamol are rare, but taking too much can cause liver damage, especially when combined with alcohol. Some medications have paracetamol as one of their ingredients, for example Percocet in the US (which contains tramadol + acetaminophen) and Citodon in Sweden (codeine + paracetamol). It is very important to be aware of the fact that taking drugs like these as well as regular paracetamol pills may result in an overdose and liver damage.

Paracetamol is most commonly sold under the brand name Tylenol in the US, and as Alvedon in Sweden.

NSAIDs (nonsteroidal anti-inflammatory drugs)

NSAID is a group of drugs that is used to treat pain, inflammation and fever. Some NSAIDs can be bought over-the-counter while others require a prescription. They are often helpful in treating chronic inflammatory conditions. NSAIDs are often used in combination with paracetamol to enhance the pain relieving effect.

The chart below shows the most common NSAIDs as well as their brand names in the US and Sweden:

NSAIDs work by blocking the activity of two enzymes called COX-1 and COX-2 that play a key part in the production of prostaglandins, which promote pain, inflammation, and fever. By reducing the amount of prostaglandins, NSAIDs also reduce pain and inflammation. However, prostaglandins also have many other functions - for instance, they control the formation of blood clots and help protect the lining of our stomach. As a result, NSAIDs can cause many side effects, especially when used regularly over an extended period of time. Some of the most common side effects are stomach pain, heartburn, indigestion, reflux, nausea and vomiting, gas, bloating, diarrhea, gastrointestinal bleeding, and stomach ulcers. NSAIDs also thin the blood and slow down blood clotting time, and increase the risk of developing cardiovascular disease and kidney damage. People who already suffer from cardiovascular or kidney disease, take blood thinners (such as warfarin) or have had stomach ulcers or bleeding problems in the past should avoid NSAIDs altogether.

Opioids

Opioids are a group of drugs that are derived from or related to the opium poppy - or, in other words, morphine-like painkillers. They have a powerful pain relieving effect, but unfortunately come with a lot of unpleasant side effects such as somnolence, drowsiness, dizziness, nausea, vomiting, and constipation. Large doses also slow your breathing and heart rate which can be fatal. In the US, prescription opioids lead to approximately 20,000 deaths every year.

Another problem with opioids is that they are extremely addictive - nearly 5 million people in the US have an opioid dependency. You may develop physical dependence even if you are careful and only take the medication as prescribed by your doctor. When you take opioids regularly, your body becomes used to them and will need increasingly higher doses in order to get the same pain relieving effect as before ( = tolerance). Eventually, you may end up with very large doses that you can't stop taking because you get severe withdrawal symptoms if you try. For this reason, the doctor who prescribes the opioids is required to follow up your treatment regularly in order to evaluate the effect of the medication and to monitor side effects as well as any signs of physical dependency or abuse. Ask your doctor for a treatment plan that says exactly how and when to take the tablets, especially if you are prescribed different ones.

Although a small proportion of people with chronic pain gets benefits from opioids, there is a lack of evidence to support the safety and efficacy of long-term opioid therapy. Recent studies show that there are many possible long-term consequences such as tolerance, addiction, drug abuse, hyperalgesia, decreased pain tolerance, emotional problems (depression, anxiety, mood swings), sexual dysfunction, decreased bowel function, constipation, nausea, dyspepsia, sleep-disordered breathing, fractures, endocrine and immune disturbance, impaired kidney and liver function, and cardiovascular problems such as arrhythmia. However, the likelihood for side-effects and long-term consequences relates to the dose and the duration of the opioid treatment. There is also an increased risk when opioids are combined with alcohol or drugs such as benzodiazepines.

Opioid tolerance

Opioid tolerance is a very common consequence of long-term opioid therapy. It is defined as a need for larger doses of an opioid in order to achieve the same level of pain relief as you did initially. (It is not the same thing as dependency or addiction, and doesn't cause any withdrawal symptoms if you stop taking the drug.)

When we take an opioid, the drug molecules bind to and activate our opioid receptors, which then starts the whole process that eventually leads to pain relief. It is believed that 2 of the main mechanisms that are responsible for tolerance are downregulation and desensitization of these receptors.

Downregulation is a decrease in the amount of receptors on the surface of our cells, which means that the cells become less sensitive to the opioid molecules.
Desensitization means that the receptors become less sensitive and don't respond as well as they used to when they are activated by the opioid molecules. They may also require a larger amount of opioid molecules ( = a higher dose) in order to get activated and actually cause a response in the first place.

In other words, your body won't respond as well to the same opioid dose as it used to, which means that you won't get the same pain relief unless you increase the dose.

Treating acute pain or flares in opioid tolerant patients can be very difficult since they require such large doses, and unfortunately, this often leads to inadequate treatment and pain relief. For this reason, some clinics use other drugs to treat flares, e.g. esketamine/ketanest.

(For more info: https://www.uspharmacist.com/article/acute-pain-management-in-patients-with-opioid-tolerance)

Opioid-induced hyperalgesia

The long-term use of opioids can lead to a condition called opioid-induced hyperalgesia (OIH) where the opioids increase the sensitivity of the body's pain receptors, which means that you become abnormally sensitive to pain (not to be confused with drug tolerance!).

How do you know if you have OIH?

The site of the injury becomes more sensitive to pain, even though your underlying condition hasn't worsened.
The pain feels like it's spreading to non-injured parts of the body.
New pain may develop without a specific diagnosis.

Unlike when you're dealing with tolerance, increasing the opioid dose won't decrease the pain - in fact, it often makes it even worse.

How can you treat OIH?

You may have to stop taking opioids completely. The pain may worsen at first because of the withdrawal from the opioids, but the OIH will stop when you're off the opioids.
You may have to switch to a different kind of opioid (like methadone or buprenorphine) but this doesn't always help.
Switching to non-opioid medications like NSAIDs, gabapentin or antidepressants may be a better choice.
NMDA receptor antagonists (e.g. ketamine/ketanest) may help block the overly sensitized pain receptors.

Antidepressants

Antidepressants are primarily used for neuropathic and nociplastic pain. Initially, it was believed that their pain relieving effect only was a result of treating depression. Today, however, we know that certain types of antidepressants actually have a direct pain relieving effect - the most common ones being tricyclic antidepressants (TCA) and serotonin-norepinephrine reuptake inhibitors (SNRI).

TCAs are an older type of antidepressants that unfortunately have a lot of unpleasant side effects when used to treat depression. One of most common TCAs is amitriptyline (Elavil in the US, Saroten in Sweden). Today, TCAs have largely been replaced by newer ones such as SSRI and SNRI which have less side effects. When used to treat chronic pain, however, TCAs are effective at much lower doses than the ones used to treat depression, which reduces the amount and severity of their side effects. There is no point in taking higher doses than those prescribed for chronic pain - they aren't more effective, but instead increase the risk of side effects. The most common side effects include dry mouth, sedation, dizziness, and blurred vision.

Another type of antidepressants that is used for chronic pain is SNRI. Common ones include duloxetine (Cymbalta) and venlafaxine (Effexor). SNRIs may be a good option for people who have both chronic pain and clinical depression. The side-effects are usually mild and go away after the first few weeks of the treatment, but the most common ones are nausea, dry mouth, dizziness, headache, and excessive sweating. Taking the medication with food may reduce the nausea.

We don't know exactly how the antidepressants work when used for chronic pain. They may increase the amount of neurotransmitters in the spinal cord, which in turns reduces the pain signals and increases the body's own ability to relieve pain.

Anticonvulsants (antiepileptics)

Just like antidepressants, anticonvulsants are primarily used to treat neuropathic and nociplastic pain. They are believed to reduce the overactivity in the nervous systems - in other words, they have a nerve-calming effect. Carbamazepine, gabapentin and pregabalin seem to be the most effective anticonvulsants when used to treat chronic pain. The side effects may vary from one anticonvulsant to another, but the most common ones are dizziness. drowsiness and nausea.

Ketamine/esketamine

Ketamine (a.k.a. Ketalar) and esketamine (a.k.a. Ketanest) are two very similar drugs that can be used to treat flares. In Sweden. Ketanest has mostly replaced Ketalar in Sweden (at least where I live and work) since it is about twice as potent and leads to less cognitive effects, so that's the one I focus on here.

Esketamine is is an anesthetic drug, which means that it is used to induce anesthesia, e.g. for surgery. However, it is a bit different from other anesthetics since it doesn't necessarily lead to a loss of consciousness, but instead causes dissociative amnesia - it creates a sensation of detachment (or dissociation) from your environment and yourself, as well as memory loss and a very strong pain-relieving effect. Since esketamine doesn't lead to respiratory depression or low blood pressure, it is often used by paramedics before performing painful procedures or loading a severely injured patient into the ambulance without causing too much pain.

In low doses, ketamine infusions relieve pain without causing any symptoms of dissociation. You may, however, experience blurred vision or feel a little dizzy or nauseous, but this often fades pretty quickly. Some hospitals and clinics use esketamine infusions to treat flares in people with chronic pain for two main reasons:

Many patients with chronic pain take opioids regularly and have developed a tolerance for opioids. Treating their flares with opioids can be a challenge since they would need very high doses in order to achieve pain relief, so esketamine may be more effective in these cases. If the ketamine infusion isn't effective enough, you can still add opioids for a stronger effect - but even if you do, you will need significantly lower doses than if you only used opioids to treat the flare.
Esketamine is an NMDA receptor antagonist, which means that it blocks NMDA receptors. The activation of these receptors is (among other things) associated with sensitization and hyperalgesia (= abnormal sensitivity to pain) as well as reduced functionality of opioid receptors, all of which lead to increased pain. By blocking the NMDA receptors, esketamine can stop the sensitization and break the cycle of pain that occurs during a flare, and its effects.

Although many anesthesiologists use and recommended esketamine to treat chronic pain flares, others have very strong negative opinions about it. I have done a lot of research and talked to many doctors in order to understand why they have such different views, and it seems like it mostly has to do with the fact that there is uncertainty about its long-term effects. Of course, I have found very contradicting information about this as well, so I can't be 100 % sure that what I write here is correct. Some studies have shown that there are possible long-term side effects of ketamine use, such as psychotic symptoms and damage to the bladder, heart, liver, stomach and intestines. However, it seems like these side effects occur in people who abuse ketamine and use it chronically (unfortunately, its dissociative effects and hallucinations have made it popular as a recreational drug). As far as I know, there is (so far) no evidence that the occasional use of esketamine to treat chronic pain flares leads to any long-term consequences.

Routes of administration

A route of administration is a path by which a drug is taken into the body, e.g. through the mouth, through the skin, or rectally. It can also be injected, either into a muscle, the fatty tissue just beneath the skin, or directly into a vein. Each route has its own specific purposes, advantages and disadvantages. The most frequently used ones are through the mouth (oral administration) or into a vein (intravenous administration).

Oral administration

Oral administration, which means that the drug is administered through the mouth, is the most common route. The medication is usually swallowed, but it can also be dissolved buccally (inside the cheek) or sublingually (under the tongue). When swallowed, it passes through the gastrointestinal tract and is taken up by the intestines or, in certain cases, in the stomach. Drugs that are administered orally come in various forms, e.g. tablets or capsules that can either be swallowed, chewed or dissolved in the mouth, liquid syrup, drops, powders, or granules. Since they have to pass through the gastrointestinal tract, it takes a while for them to kick in. However, they also take longer to leave the body when compared to injections, which means that their effect lasts longer.

Drugs that are taken orally can be divided into two groups: immediate (a.k.a. conventional) release (IR) and extended (a.k.a. sustained) release (ER). IR medications release the entire dose directly. This leads to a relatively fast and powerful onset, but they also leave the body rather quickly. In other words, the concentration of the drug in your bloodstream "peaks" and "valleys". ER medications, on the other hand, release the dose slowly over time. They aren't as quick-acting as IR drugs, but their effect lasts longer and they help you avoid the peaks and valleys. If you take ER medications regularly, the concentration level in your bloodstream will stay more or less constant at all times, a concept known as "steady state".

The graph below shows the difference between IR (conventional release) and ER (sustained release) medications:

The following graph (from drpain.com) shows what the drug concentration in your bloodstream (serum level) looks like if you take IR and ER medication regularly. The gray area is the serum level that you want to reach. Lower levels aren't enough to relieve the pain, and higher levels cause too many side effects. As you can see, ER drugs make it easier to stay within the gray area.

As always, you should never take more medications than what is necessary. If you can manage your chronic pain by only taking the occasional IR painkiller, that is obviously great. However, if you often experience severe pain and frequent flare-ups, taking ER painkillers regularly may actually be a better option for two main reasons:

The constant amount of the drug in your bloodstream will help prevent pain flares - and stopping these from happening in the first place is a lot easier than trying to treat them once they have already occurred. As a bonus, this strategy will also decrease the total amount of medication that you end up consuming in the long run.
ER medications lower the risk of drug addiction and abuse. One of the reasons for this is that they don't have that peak that IR drugs have. If we take opioids as an example, this peak is actually the euphoric high that a lot of people experience (especially in large doses) and that easily causes opioid abuse and addiction.

It is important to know that taking ER painkillers regularly doesn't necessarily mean that you can't take IR painkillers as well. Even though the ER drugs decrease the amount and intensity of pain flares, it is often impossible to get rid of them altogether. When they do occur, your regular ER painkillers may not be effective enough. In these cases, it is perfectly fine to use IR drugs as well during a short amount of time. However, if you regularly have to take IR analgesics because the ER ones aren't effective enough, it might be a good idea to increase the ER dose instead.

Intravenous (IV) administration

There are several different types of injections, the most common ones being subcutaneous (into the fatty tissue under the skin), intramuscular (into a muscle), and intravenous (into a vein) injections. IV injections are often preferred as they are less painful.

When a drug is injected straight into a vein, the entire dose enters the bloodstream directly, causing a much quicker and more powerful onset of action than that of IR drugs taken orally. However, the effect doesn't last very long. For example, the analgesic effect of IV morphine begins almost instantly, reaches its peak after approximately 15 minutes, and lasts for approximately 2 hours. For this reason, IV analgesics such as morphine are a good option to treat severe acute pain or flares. They are not, however. a long term solution for chronic pain.

Drugs that are administered intravenously can also be given as a continuous infusion. Instead of injecting the entire dose directly, an infusion will release the medication slowly over a longer period of time. For instance, you may want to administer 100 ml of a certain drug over one hour, which would be a rate of approximately 1.67 ml per minute. This is quite similar to the way ER drugs work, but a continuous intravenous infusion will help you reach a much more exact steady rate.

When administered intravenously, the side effects of the medications are often more severe than when taken orally. For example, high doses of IV morphine easily lead to respiratory depression and can even be life-threatening.