Chronic Pain and Substance Use Disorders Have Shared Genetics

By Fred Schwaller | May 16, 2024 | Posted in

A new study includes data from more than 800,000 people with chronic pain, with lessons for the migraine field, too.

People with chronic pain disorders have a higher chance of developing substance use disorders (SUDs) than others without pain. Part of the reason is that current treatments for pain are inadequate, leading to misuse of substances like alcohol, cannabis, or opioids as individuals search for a way to manage their pain. But now, a new study shows that chronic pain and SUDs have a shared genetic basis that also explains the association between the two.

The study, from lead author Dora Koller, senior author Renato Polimanti, both of Yale University, New Haven, US, and colleagues found strong genetic relationships, of a causal nature, between chronic pain experienced at multiple body sites (multisite pain) and SUDs. But not all SUDs were the same: Cannabis use disorder had a particularly strong genetic link with chronic pain, compared to alcohol, tobacco, or opioids.

“We already knew that chronic pain is linked with substance use disorders from epidemiological studies, but this shows it on a genetic level, too. It shows that people with a genetic predisposition to chronic pain may have more risk of developing a substance use disorder,” said Luda Diatchenko, McGill University, Montreal, Canada. Diatchenko is a pain geneticist but was not involved in the new research.

The study, which the authors say is the first large-scale investigation to look at potential associations between multisite pain and multiple SUDs, appeared online ahead of print on February 15, 2024, in Molecular Psychiatry.

Genetic links
To evaluate the genetic basis of comorbid multisite chronic pain and SUDs, the researchers used data from previous genome-wide association studies (GWAS), which are investigations that identify common genetic variants associated with a trait or disease of interest. Those variants are known as single nucleotide polymorphisms, or SNPs, which are single base changes to DNA.

Those previous GWAS included participants from three cohorts: The UK Biobank, which contains information on SNPs associated with multisite chronic pain, and the Million Veteran Program and Psychiatric Genomics Consortium, which have identified SNPs associated with SUDs. Together, those datasets included roughly 800,000 people, giving the researchers a large sample size to work with for their new study.

“We looked at the genetic links of multisite chronic pain with multiple substance use disorders – alcohol, cannabis, tobacco, and opiates. It’s important to say we’re looking at substance use disorders, and not general substance use. Not everyone using substances generates a disorder, and they are two distinct phenomena,” Polimanti told MSC.

The first part of the study aimed to assess whether there were SNPs in common between patients with multisite chronic pain and SUDs. The analysis found moderate genetic correlations between all the SUDs and chronic pain. These findings are in line with previous studies, and so neither the authors nor Diatchenko found these initial results particularly surprising.

“After all, we’ve known about the correlation between the two for some time. There are strong genetic correlations between chronic pain and many psychological traits like anxiety and depression, as well as substance use disorders, but it’s good to put a number on these correlations with such a strong dataset,” said Diatchenko.

Seeking direction
But correlation does not equal causation, so the team took an additional step by using Mendelian randomization. This is a method that would allow the researchers to identify not only causative links between chronic pain and SUDs, but to address directionality, too: Do SUDs cause chronic pain, or does chronic pain cause SUDs?

The answer was both, but the causative effect of chronic pain on SUDs was, overall, much stronger than the other way around.

“This was a cool part about this paper – they show it’s much more that chronic pain leads to substance use disorder rather than substance use disorder leads to pain. This was a very solid result,” said Diatchenko.

The study also revealed differences between the various SUDs. Cannabis use disorder had a particularly robust genetic relationship with chronic pain, followed by alcohol use disorder and problematic tobacco use.

“The cannabis result is particularly interesting because, from an epidemiological point of view, individuals suffering from chronic pain often report a significant improvement when they start using cannabis, at least at the beginning,” first author Dora Koller told MSC via email.

However, opioid use disorder was not significantly linked genetically with chronic pain. This was somewhat surprising, considering the widespread use of opioids to manage chronic pain, particularly in the US. But the researchers say this could be due to the limited statistical power of the previous GWAS to detect SNPs associated with opioid use disorder; GWAS require large sample sizes to do so.

“But we have very powerful data for the other substance use disorders, so it’s clear the effects we see are due to shared biological mechanisms between pain and the other SUDs,” said Polimanti. A “powerful dataset” can be explained as data generated from a cohort of participants large enough to observe a statistically meaningful effect, Polimanti added.

Another factor, which the authors acknowledge in their paper, was that a large amount of the data used in the study was from the UK, where opioids are less commonly prescribed to treat chronic pain.

Single genes, multiple effects
Next, the researchers performed a pleiotropy analysis. Pleiotropy is the phenomenon of a single gene having an effect on more than one phenotype.

The study found two individual SNPs that showed significant pleiotropy, with each one associated with both multisite chronic pain and all SUDs considered in the study. One of these genetic variants was found in a gene called CADM2 which, among other functions, plays a role in impulsivity and personality traits. The other variant appeared in IHO1, a gene associated with meiotic recombination, which is a process important for the segregation and mixing of chromosomes.

These findings are important first steps in understanding the shared biology between chronic pain and SUDs. However, it’s questionable how much real impact these individual SNPs have.

“I’m less excited by the particular SNPs they found because I don’t believe they are the SNPs. These phenotypes are highly polygenic, so thousands of genes are contributing. I’m sure these SNPs are contributing, but their actual effect is very small, and there are many other genes involved,” said Diatchenko.

The authors agreed.

“This is a complex genetic interaction [between chronic pain and substance use disorders] and not a monogenic disorder. These SNPs are just small pieces of the puzzle, and there will be many more pieces to discover,” said Polimanti.

Looking to brain imaging
In the final part of the study, the team investigated possible associations between the SNPs in CADM2 or IHO1 with particular brain imaging phenotypes; imaging information was available from more than 33,000 participants in the UK Biobank.

The genetic variant in CADM2 was associated with alterations in 12 brain imaging phenotypes, which included changes in the cerebellum and amygdala. While the data aren’t conclusive evidence of biological changes associated with both chronic pain and SUDs, the authors said their work is a good first step to look at their shared biology.

“The brain imaging phenotypes provide links between the genetic components and specific brain regions – the cerebellum and amygdala – which we know are involved in pain and substance use disorders. They give us more information about shared biology between the two phenomena,” Polimanti said.

What about migraine and SUDs?
The study did not specifically look at the genetic links between headache disorders and SUDs, since the data sources used in the study did not have information about specific pain conditions, but rather only about pain at particular body sites (including the head and face). But, nonetheless, the results have some relevance to migraine, considering the relationship between chronic pain and migraine.

“There is some shared biology between chronic pain and migraine, but some important distinctions, too. It would be interesting to understand if what we found here in multisite chronic pain is similar in the context of migraine, and what differences there are, too,” said Polimanti.

Diatchenko held a similar opinion.

“The findings [for migraine and its possible association with SUDs] should be in the same realm as chronic pain, but they might be different. All chronic pain conditions are strongly correlated genetically and epidemiologically – if you have one, you most likely have another one – but migraine stands a little separately from this and has different genetic links [than chronic pain], so new analyses would need to be done,” she told MSC.

One difficulty, however, is the issue of the statistical power of the datasets available.

“The first thing we need to do is see if we have the right data to test the hypothesis. For migraine, we need to see if the genetic data we have are powerful enough. That’s why we went for multisite chronic pain in the first place – the available datasets are very powerful,” said Polimanti.

In the meantime, the authors say the study highlights the need for clinicians and people with all types of pain to be aware there could be genetic risks for developing SUDs, along with the environmental risks that are known to play a role as well.

Fred Schwaller, PhD, is a freelance science writer based in Germany. Follow him on Twitter @SchwallerFred

Image credit: 123RF Stock Photo.

Reference
Pleiotropy and genetically inferred causality linking multisite chronic pain to substance use disorders.
Koller et al.
Mol Psychiatry. 2024 Feb 15. Online ahead of print.

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Fred Schwaller is a science writer and communicator based in Berlin, Germany. Fred spent a decade in pain research during his doctoral degree at University College London, UK, and his postdoc at the Max Delbrück Centre in Berlin, Germany. After transferring to science communication in 2020, he has been writing and podcasting about life sciences and medicine, specializing in somatosensation and pain. Follow him on Twitter @SchwallerFred.

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