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Why don’t painkillers work for everyone? A guide to pharmacogenetics-based chronic pain treatment

Chronic pain is notoriously hard to treat. Affected individuals endure pain for months or years, trying desperately to find a remedy to take the pain away. Unfortunately, less than 30% of patients respond, even with the best treatment. It may take several months to reduce the pain to tolerable levels. This is often because drug therapy is not optimized to a patient’s unique genetic makeup, which determines how medications are metabolized. Pharmacogenetic tests offer prescribers the opportunity to personalize chronic pain medication therapy to match the patient’s genetic makeup and achieve better results. This article discusses the different chronic pain treatment options for different types of pain and how pharmacogenetic tests like Pillcheck can help to improve chronic pain management.

Pain medications include opioids, antiepileptics, Tricyclic antidepressants (TCAs), Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs), and Nonsteroidal anti-inflammatory drugs (NSAIDs). Additionally, functional rehabilitation, physiotherapy, cognitive behaviour therapy (CBT) and acupuncture are proven to improve the quality of life for people with chronic pain. Medical cannabis is now being studied as another option for chronic pain, but the level of evidence to recommend cannabinoids for chronic pain treatment is still low.

Each treatment type has associated risks summarized in the chart below.


Commonly used opioid-based medications include codeine (Tylenol #3, Tylenol #4), morphine, tramadol, oxycodone, hydrocodone, hydromorphone, and fentanyl. Opioids are used for acute perioperative pain management before, during and after surgery. However, the use of opioids for chronic pain treatment must be limited to refractory pain and palliative care. Prolonged use of opioids is counterproductive as opioids increase a person’s sensitivity to pain, requiring drug dosage increases to counteract the tolerance, thus increasing the risk of overdose and addictions. One study, the Prescribing Analgesics Comparative Effectiveness trial, compared a stepped approach among patients with osteoarthritis and found that treatment with opioids was not superior to treatment with nonopioid medications for improving pain-related function.

There are two types of opioid medications:

  1. Pro-drugs such as codeine (Tylenol #3, Tylenol #4), tramadol, oxycodone, and hydrocodone, which require biotransformation to more active forms by the CYP2D6 liver enzyme in order to enhance binding to opioid receptors and suppress pain.
  2. Bioactive compounds such as morphine, hydromorphone and fentanyl that act directly on opioid receptors, and are independent of CYP2D6 activity.

Both pro-drugs and bioactive opioids are available in fast- and slow-release formulations. Slow-release formulations are thought to provide analgesic effect over a longer timeframe, while fast-acting opioids are used for breakthrough pain control.

Response to opioids is impacted by genetic variations and by other medications being taken. Drugs that block CYP2D6 activity such as antidepressants, beta-blockers, and even allergy medications can reduce the activation of oxycodone, tramadol and codeine to active compounds and reduce the analgesic effect. People with inherently reduced or absent CYP2D6 function do not achieve adequate pain control with pro-opioid medications. Contrastingly, people who have elevated CYP2D6 activity are at risk of accidental overdose because they convert codeine to morphine too quickly. These people, called Ultrarapid Metabolizers, are at higher risk of sudden death if an antidepressant or another drug metabolized by CYP2D6 is stopped while continuing treatment with oxycodone or tramadol due to released inhibition of the CYP2D6 enzyme. Randomized clinical trial (Cavallari at al., 2019) demonstrated that for people with reduced CYP2D6 activity, a switch to alternative therapy lowers pain scores.

The use of opioids should be carefully monitored in people with a history of mental health conditions, especially those treated with atypical antipsychotics due to increased risk of psychosis and addictions.

Additionally, people who carry mutations in the opioid receptor mu, encoded by the OPRM1 gene, experience a reduced response to opioids and may need higher doses to achieve adequate pain control. Delirium and opioid-induced constipation are a significant problem for elderly patients. Although NSAIDs and TCAs are not recommended for older individuals, pharmacogenetic tests can help to assess which pain medications are better suited for your patients.


Nonsteroidal anti-inflammatory drugs are a drug class that reduce pain, decrease fever, prevent blood clots and, in higher doses, decrease inflammation. NSAIDs such as ibuprofen, celecoxib, flurbiprofen, and diclofenac are the first-line treatment for inflammatory pain. Inflammatory pain is characterized by elevated biomarkers of inflammation, such as C-Reactive Protein (CRP) and autoimmune antibodies. NSAIDs are not well suited for long term use due to the significant increase in NSAID-induced GI bleeding, and increased risk of heart attack and stroke. People with reduced CYP2C9 activity have a significantly increased risk of GI bleeding. Drugs with long half-life such as piroxicam and tenoxicam are contraindicated even for intermediate CYP2C9 activity. Refer to the CPIC guideline on NSAID selection and dosing (


Gabapentin (Neurontin) and pregabalin (Lyrica) are prescribed for neuralgia caused by shingles and diabetes, but these medications are effective for less than 30% of patients. Both gabapentin and pregabalin are even less useful for other types of neuropathic pain. Antiepileptics, in rare cases, can cause severe skin toxicity called Stevens-Johnson syndrome (SJS). The risk of such toxic reactions is determined by specific immune histocompatibility types. HLA-B*15:02 risk allele is common in Asian populations while the HLA-A*31:01 is relevant for Japanese and Europeans. Both gabapentin and pregabalin are eliminated from circulation by the kidneys without metabolic transformation. Therefore, genetic liver enzymes do not impact response to these medications.

Tricyclic Antidepressants

TCAs include drugs such as amitriptyline (Elavil), amoxapine (Asendin), desipramine (Norpramin), doxepin (Silenor), imipramine (Tofranil), nortriptyline (Pamelor), protriptyline (Vivactil), and trimipramine (Surmontil). Amitriptyline and other TCAs are one of the most effective treatments for depression and chronic pain. However, TCAs often have poor tolerability. TCAs have a strong anticholinergic effect, i.e. impacting digestion, urination, salivation, and movement, and other side effects. TCAs are metabolized by both CYP2C19 and CYP2D6 enzymes. The CPIC guidelines indicate that patients who are Poor or Ultrarapid metabolizers for either 2D6 or 2C19 should not be treated with TCAs, while a 25% dose reduction is recommended for people with reduced CYP2C19 or CYP2D6 activity. Pharmacogenetic testing can assess whether TCAs are appropriate for patients.

Serotonin-Norepinephrine Reuptake Inhibitors

SNRIs like venlafaxine (Effexor XR), desvenlafaxine (Pristiq), duloxetine (Cymbalta), levomilnacipran (Fetzima), trazodone (Desyrel) are antidepressants that can also be used for chronic pain. SNRIs have a lower impact on libido than SSRIs and are considered to be useful for people with fibromyalgia, and central pain, particularly for patients experiencing depression symptoms. Venlafaxine’s activation is dependent on CYP2D6 activity; people with significantly reduced enzyme function can try desvenlafaxine or other SNRI. Levomilnacipran and trazodone are cleared by CYP3A4 and might be less tolerated by people with inherently reduced activity of this enzyme. Antibiotics, other drugs, and grapefruit juice can also inhibit CYP3A4 function and cause side effects when coadministered with levomilnacipran and trazodone. A dose reduction may help to improve tolerability. The CYP3A4 enzyme is known to be induced by phenobarbital, phenytoin, rifampicin, St. John’s Wort and glucocorticoids – concurrent use of these medications will reduce the clinical effectiveness of levomilnacipran and trazodone.


Cannabidiol (CBD) is approved for the treatment of rare forms of epilepsy and is also in trials for chronic pain treatment. Although cannabidiol is relatively safe and thought to have an anti-inflammatory effect, THC containing formulations can cause psychotropic side effects. Cannabidiol is metabolized by CYP2C9, CYP3A4 and CYP2C19 enzymes, and inhibits CYP2D6 enzyme, hence has an extensive list of drug-drug interactions. Please consult with an expert pharmacist if you are considering medical cannabis for a patient taking several medications. Pharmacogenetic testing can assist in assessing whether cannabinoids can be used to augment the pain treatment.

Pharmacogenetic tests, including Pillcheck, can be reimbursed through some workplace benefits plans and may be eligible for coverage through disability claims services. If your patient is suffering from poor control of chronic pain, consider getting Pillcheck. Our expert clinical pharmacists are specially trained in pharmacogenetics and will review your patient’s medications and provide recommendations on how to optimize the treatment plan.


  • Opioids are considered the “last option” for chronic pain treatment, and nonopioid medications should be prescribed first.
  • Tolerability and response to pain medications is determined by variations in the liver enzymes and drug target genes, and drug-drug interactions.
  • Pharmacogenetic testing provides valuable insights for prescribers in assessing which pain medications will be most effective for each patient.


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CPIC guideline for NSAID selection and dosing

Sostres C and Lanas A. Appropriate prescription, adherence and safety of non-steroidal anti-inflammatory drugs. Med Clin (Barc). 2016; 146(6): 267-272.

CPIC guideline for TCAs

Cavallari LH., et al Multi-site investigation of strategies for the clinical implementation of CYP2D6 genotyping to guide drug prescribing Genet Med. 2019 Oct; 21(10): 2255–2263.

Response to “Opioids for chronic pain”. Jason W Busse, Associate Professor, McMaster University, CMAJ.

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