Priority Topic: Chronic Disease & Priority Topic: Palliative Care

Key Feature 3a: In patients with chronic disease: Actively inquire about pain.
Skill: Clinical Reasoning
Phase: History

Key Feature 3b: In patients with chronic disease: Treat appropriately by:

• Titrating medication to the patient's pain
  
• Taking into account other treatments and conditions
  (ex: watching for interactions)
  
• Considering non-pharmacologic treatment and
  adjuvant therapies
  

Skill: Clinical Reasoning
Phase: Treatment, Hypothesis generation

Palliative Care

Key Feature 4: In patients with pain, manage it (ex: adjust dosages, change analgesics) proactively through frequent reassessments and monitoring of drug side effects (ex: nausea, constipation, cognitive impairment). 
Skill: Clinical Reasoning
Phase: Treatment, Follow-up

The standard general approach to pain control is based on the World Health Organization's Pain Ladder, with the diagram and information below coming from "Palliative medicine: A case-based manual" by Doreen Oneschuk, Neil Hagen, and Neil MacDonald. The "ladder" was designed with cancer pain in mind, but it tends to provide the framework for pain management for people with all sorts of acute and chronic sources of pain. The basic idea is that for mild pain you start with non-opioid medications, with specific choice depending on the type of pain and patient characteristics. It is important to actively inquire not just about the presence of pain, but also about the quality of the pain in patients in order to treat it most effectively. Not illustrated as part of the pain ladder but equally important are also nonpharmacological interventions that can be useful in alleviating pain. As pain increases in severity, the choice of pain medication and/or dose ought to increase accordingly. Adjuvants (medications originally developed for reasons other than to improve pain, but that can also alleviate pain as a secondary effect, depending on the type of pain) can also be very useful when indicated. Poor pain control can have a significant negative impact on quality of life, and we have lots of tools in the box to work to mitigate this source of distress. It is important to continue to reassess patients experiencing pain or receiving therapy for it, to ensure that pain is in fact controlled, as well as to monitor for side and adverse effects.

Nonpharmacological therapies to consider starting, in the context of mild pain and patients who are motivated to try them, or to consider adding on to pharmacological treatments for added pain relief, could include:

• Application of heat or cold
• Exercise
• Massage
• Relaxation therapies (including meditation, guided imagery, music and art therapy, animal therapy)
• Acupuncture

There are of course many others beyond this brief list. In the setting of cancer, for example, radiation therapy may be an option (although much less benign) to improve pain control.

Common non-opioid medications for mild pain include acetaminophen and NSAIDs (ex: naproxen, ibuprofen, diclofenac, ketorolac). 

• Acetaminophen works on the perception of pain at the level of the brain. It tends to be used first line as it is has minimal risk of harm. It is, however, metabolised by the liver, so it should not be used in patients with impaired liver function or who consume excess alcohol (3 or more drinks daily). It is available in oral and rectal preparations, and can be taken as needed or around the clock.
• NSAIDs work by inhibiting prostaglandin synthesis, acting peripherally to decrease the release of inflammatory mediators and associated pain signals. When pain is secondary to an inflammatory process, they may theoretically be preferred over acetaminophen. They are generally safe to use short-term in the otherwise healthy person, but carry certain risks if they are taken for a prolonged period of time in a dose-dependent fashion. The main risks are gastrointestinal bleeding (which is why any patient who is going to take an NSAID regularly for more than 1 week should also be on a gastroprotective agent), renal impairment (patients with compromised renal function or who are at increased risk of this, such as patients with diabetes mellitus or the elderly, should avoid the use of NSAIDs), and abnormal hemostasis (predisposing patients to more significant bleeding should they have a reason for a bleed). NSAIDs can generally be found in any type of preparation depending on the specific agent selected. For inflammatory musculoskeletal pain, diclofenac gel can be prescribed without risk of the above adverse consequences.

For pain that is sufficiently severe and that cannot otherwise be controlled (with non-opioids, adjuncts, and nonpharmacological modalities), treatment with an opioid may be indicated. Opioids exert their analgesic effect mostly by agonising mu opioid receptors in the brain. Commonly prescribed weak opioids include codeine and tramadol, and commonly prescribed strong opioids include morphine, hydromorphone, oxycodone, fentanyl, and methadone.

General principles of opioid initiation and titration include having a regular dosing schedule (initially starting with a short-acting preparation until the baseline pain is controlled) with a prescribed breakthrough dose for pain to be taken as needed for acute exacerbations (generally prescribed to be taken as much as every 1 hour, or in the setting of opioids with a very rapid half life, up to every 30 minutes or so). The degree of pain control as reported by the patient along with the number of needed breakthrough doses in a given 24 hour period indicates whether or not there is a need to adjust the baseline opioid dose. As a general rule of thumb, if greater than 3 breakthrough doses in a 24 hour period are needed, unless this is attributed to being incident pain (aggravated by a specific event such as movement that would not otherwise be present at baseline), then an increase in the baseline opioid dose is warranted. The amount to up-titrate can be calculated by adding up the total quantity of opioid needed in the last 24 hour period (baseline and amount of breakthrough used), calculating the conversion to the new choice of opioid based on number of morphine equivalents, and dividing this quantity so that it is given over the next 24 hour period as the scheduled dose. And then a new quantity of breakthrough pain medication is prescribed, and a rule of thumb for this is dosing it at about 10% of the total daily scheduled amount of opioid to be given over the next 24 hour period. 

On the flip side, when patients report good pain control, with minimal to no use of doses required for breakthrough pain, the patient can be gradually weaned down as tolerated. 

Side effects of all opioids are generally the same (though they may occur to different degrees depending on the formulation, dose, and patient factors), and they most commonly include transient nausea, transient drowsiness, and constipation that is not transient and that lasts as long as the opioid is being taken. If they are given in a high dose too quickly, they can cause respiratory depression, but when prescribed responsibly in small doses with gradual up-titration, this concern is mitigated. For the nausea, an antiemetic can be prescribed either to be taken routinely or as needed, and for the constipation the patient will likely need to be on a regular dose of laxative medication. See my next post for more detail on these options.

Besides the above side effects that can occur when any opioid is used, there is also the phenomenon of opioid neurotoxicity that can occur. Briefly, this is a situation in which patients can develop altered mental status (ex: delirium, agitation, somnolence), vivid or unpleasant dreams, delusions/hallucinations (usually visual), and increased pain perception (ex: allodynia or hyperalgesia). Myoclonic jerks and seizures can also occur. In the setting of suspected opioid neurotoxicity, rotating to a different opioid is warranted (other options include simply changing the route by which the current opioid is delivered, decreasing the dose of the current opioid and adding an adjuvant, or just treating the toxic symptoms themselves; rotating the opioid is generally the preferred option). This is done by adding up the total number of morphine equivalents a patient has on board in a given 24 hour period, calculating the equivalent dose in the opioid to which the patient is being rotated to, reducing this dose by 25%, and dividing the dose to be scheduled throughout the day as the half-life of the new opioid indicates.

​Opioid options include:

• Codeine
  • Codeine is a pro-drug, which means it needs to be converted to its active form once ingested in order to have an analgesic effect. However, up to 10% of people do not have make the enzyme needed to do this, so the analgesic effect of this medication can be limited to that of a placebo effect in some people. 
• Tramadol 
  • Tramadol produces analgesia by its mu-agonist activity, but it also reduces pain through its dual action of preventing serotonin and norepinephrine reuptake as well. This means it must be used with caution in patients who are taking medications that also reduce the reuptake of serotonin (as is common with many antidepressants) as there is an increased risk of serotonin syndrome. It must also be used with caution in patients who have an increased risk of seizure. A major downside of this medication is expensive and not covered by most provincial drug plans. Although my preference is not to use codeine because it may be ineffective in some people, I would trial codeine for moderately severe pain in the outpatient population if the cost of tramadol is prohibitive for the patient in front of me.
• Morphine
  • The prototypical medical opioid, morphine is a strong opioid analgesic as it has strong affinity to the opioid mu receptor. It is a derivative of the naturally occurring opium  from the poppy plant. 90% of it is metabolised by the liver, and its metabolites (some active, some causing neurotoxic side effects) are excreted really. For patients with renal insufficiency it must be used very cautiously, or more ideally an alternative opioid should be selected. It is available in short-acting versions given every 4 hours or every 1 hour for breakthrough pain. It is also available in long-acting versions that can be given every 12 hours or once every 24 hours in its even longer-acting form.
• Hydromorphone
  • Morphine 2.0, this is a semisynthetic morphine derivative that is about 5 times more potent than morphine. It may have less neurotoxic metabolites, with a reduced risk for the associated side effects. This is my go to strong short-acting opioid. It has pretty well the same formulations available as its sister morphine.
• Oxycodone
  • Also a highly-potent semisynthetic compound, this opioid is approx 1.5-2 times as potent as morphine. Some of its activity is secondary to some of its active metabolites, and similar to codeine, this requires liver enzymes that approximately 5-10% of the population do not possess for genetic reasons. It is only available by mouth in Canada, which also limits its utility.
• Fentanyl
  • Infamous for its deadly impact on the streets in the unprecedented and ongoing Fentanyl Crisis, this opioid is undeniably helpful to the clinician who is helping patients cope with severe pain. It is approximately 100 times more potent than morphine! It has a quick onset of action, but also a short-half life, at least when it is prescribed parenterally (including through the sublingual route). While this can be beneficial for acute breakthrough pain control that is short lasting, it's permanent home in the palliative toolkit is mostly for its role in providing long-acting pain control through its transdermal application (aka the fentanyl patch). The only opioid that is administered this way, this is an excellent way of providing pain relief to patients who have stable pain control and who are unable to tolerate other forms of opioid administration (ex: if they cannot tolerate medications by mouth, this provides a pain- and hassle-free way to provide pain relief compared to repeated injection as the other alternative). The patch lasts 72 hours, and so only needs to be replaced every 3 days. It also seems to have less neurotoxic side effects than the strong opioids listed above, and so renal insufficiency is not as significant of a concern. Because the short-acting version is so very short, once a patient has stable pain control on a fentanyl patch, typically they will have one of the other strong opioids on board in a short-acting formulation for breakthrough pain. 
• Methadone
  • A synthetic opioid most known for its use in the context opioid addiction, it provides approximately 10 times the analgesic effect as morphine. The actually conversion depends on the dose being used; the relationship is not linear due to its lipophylicity and subsequent storage in the body's fatty tissues. This factor also gives it a somewhat unpredictable half-life, and can only be prescribed by physicians with special training in its use. Generally, it is prescribed to be given every 8-12 hours. It is affordable, and it is unique in that while it agonizes the mu opioid receptor, it also seemingly provides neuropathic pain relief through its activity as an NMDA (glutamate) receptor antagonist. It has no known active metabolites, so is a good choice in a patient with renal failure, and due the unique way it is stored in the body's fat, it is a good choice for the patient who receives hemodialysis. It is metabolised by the liver, so in the setting of hepatic disease, the dose ought to be adjusted cautiously.

Some adjuvants that may be useful in pain management, particularly in the palliative care setting:

• Dexamethasone is a corticosteroid that helps to reduce inflammation, particularly useful in reducing pain associated with peritumoural edema (commonly used in the setting of headache secondary to brain metastases) as well as bone pain (for which bisphosphonates are also a mainstay)
• Tricyclic antidepressants (ex: nortriptyline), rarely prescribed as antidepressants now given the superiority of newer options, they still have much utility in treating neuropathic pain, particularly that which is characterised as constant.
• Gabapentin, originally developed as an anticonvulsant, is also a mainstay in the treatment of neuropathic pain, and it may be particularly indicated in the neuropathic pain characterised as intermittent and sharp/shooting.
• Ketamine is a big gun drug that's been around the block and that has fallen out of but now back in favour with many physicians today. It is a medication often used for induction in anesthesia with associated strong analgesic properties and dissociative side effects. Typically this medication is prescribed in consultation with an anesthesiologist or other pain specialist. 
• Hyoscine for colicky bowel or genitourinary pain. Not to be used if there is suspicion of complete obstruction. 
• Methotrimeprazine is an antipsychotic with analgesic properties that can be a useful adjuvant in the setting of pain complicated by agitation or delirium