Brain Changes Wrought by Opioid Analgesics

A newly-reported imaging study found that oral morphine administration in patients with chronic low back pain altered gray matter thicknesses in several brain structures. While the authors imply that these neuroplastic changes might be detrimental, it seems equally likely that long-term opioid administration restores the pain-altered brain to a more normal, healthy state.

As opioid analgesics are increasingly prescribed for chronic noncancer pain, it is important to understand potential effects of these agents in changing neurobiological structure and function of the brain. Researchers at Stanford University, California, conducted a longitudinal, MRI (magnetic resonance imaging) study examining 10 individuals with chronic, moderate-to-severe, nonradicular low back pain who were administered long-acting oral morphine (MS-Contin) daily for 1 month [Younger et al. 2011]. Brain imaging was conducted immediately before and after the morphine administration period, and a third time at an average follow-up of 4.7 months. Similar imaging was conducted on a separate group of 9 subjects with chronic low back pain, receiving a blinded placebo substance for the same time period, to serve as a control group for determining if any brain changes might occur that were not specific to opioid administration.

Results reported in the August 2011 edition of the journal PAIN indicate that 13 brain regions in morphine-administered subjects evidenced significant volumetric change, and the degree of change in several regions correlated with morphine dosage. Dosage-correlated volumetric, gray matter decreases were observed in limbic areas, primarily in the right amygdala. On the other hand, dosage-correlated volumetric increases were seen in select limbic and cortical structures: the right hypothalamus, left inferior frontal gyrus, right ventral posterior cingulate, and right caudal pons.

Follow-up MRI scans demonstrated that many of the morphine-induced neuroplastic changes persisted over time. Conversely, in control subjects, there were no significant morphologic changes at any time point, suggesting that brain changes occur relatively rapidly in humans as a result of new exposure to prescription opioid analgesics [ie, morphine, in this case]. The authors conclude that these changes in gray matter volume add to a growing body of literature showing that opioid exposure causes structural and functional changes in reward- and affect-processing brain circuitry.

COMMENTARY: The researchers characterize their investigation as a pilot study; however, the small numbers of enrolled subjects are typical of most brain imaging research trials. Larger follow-up investigations are rarely conducted in such cases and it could be imprudent to generalize externally from these small studies to larger populations of patients.

In this present study, there were potentially important demographic variations within the treatment and control groups as well as significant differences between groups. Control subjects were all males and significantly younger (mean age 30 years) than treatment-group participants (mean age 47 years; 60% female). In the treatment group, duration of pain ranged from 2 to 25 years, pain severity ranged from 2.5 to 6.5 on a 10-point scale, and the total amount of morphine administration per individual during the study ranged from 165 mg to 3,120 mg (a maximum of 120 mg/day was allowed). Considering these differences, the study limitations, and within group data variability it would seem difficult to confirm either statistically or clinically valid conclusions.

Prior evidence has demonstrated that chronic pain itself influences important changes in brain structure and function [as discussed in the Pain-Topics UPDATES series on “Pain & the Brain” here]. In this current study by Younger and colleagues, significant changes were observed in brain structure attributable to morphine administration; however, a most critical question is: Were these morphine-induced brain structure alterations potentially harmful or, equally likely, of benefit in helping to reverse the neurobiological damage of chronic pain and returning the brains of suffering patients to a more normal state?

This research investigation does not answer that question. But the authors do concede that “…some of the changes we observed could reflect clinically beneficial effects of opioid treatment. Changes in brain volume are not necessarily indicative of harm, so future studies should focus on how opioid-related brain changes are associated with positive and negative clinical outcomes.” Perhaps, future studies also will make comparisons with brain structure in “normal subjects” without pain, which this current investigation did not do, to determine if opioid administration does indeed reinstate more normal neurobiology.

It is curious that the researchers appear to be searching from the outset for evidence of opioid-induced changes in the human brain possibly relating to harmful effects, such as addiction, cognitive impairment, emotional imbalance, and/or hyperalgesia. For example, they state, “…research may reveal specific brain changes associated with the negative effects of long-term opioid use. …. Also, information linking brain changes to behavioral outcomes may allow us to develop predictive models of risk for negative opioid effects.”

Rather than a hypothesis of “negative effects” and “risks,” researchers could just as easily approach the subject from a less biased and more positive perspective, exploring via imaging studies the plausible neurobiological benefits of opioids in the setting of chronic pain. However, extending findings with morphine to opioids as a class, as this present study does, could be overreaching unless supported by research exploring different opioid agents.

REFERENCE: Younger JW, Chu LF, D’Arcy NT, et al. Prescription opioid analgesics rapidly change the human brain. PAIN. 2011(Aug);152(8):1803-1810 [abstract here].