CATR: What kind of work do you do, Dr. Manhapra?
Dr. Manhapra: I run a clinic at the Hampton VA Medical Center helping patients with treatment-resistant chronic pain and disability. We see patients who have trialed many pain management treatments including injections, procedures, surgeries, and psychological pain treatments, all of which have failed. They tend to be severely disabled and exhibit the interplay of substance use disorders (SUD), psychiatric disorders, and medical disorders along with chronic pain.

CATR: The population you describe sounds specific and rather complex. Do our readers see them in the office?
Dr. Manhapra: Yes, this population is increasingly prominent. There are around 30 million people nationally with moderate to severe pain daily or near daily. About 10 million of them have high-impact chronic pain, which means they have chronic pain and at least 1 disability: activity limitation or limited participation in life functions (Krebs EE et al, PLoS One 2020;15(4):e0230751). Of this group, about 85% do not work. About 25% of them cannot even do household chores. So, it is a large population with high utilization of psychiatric and primary care services.

CATR: How does this population map onto the population with opioid use disorder (OUD)?
Dr. Manhapra: There are 2.5 million people with OUD in the country, and about two-thirds of them have significant chronic pain (Hser YI et al, J Subst Abuse Treat 2017;77:26–30). My experience has been that the majority of those patients with OUD and chronic pain developed their pain after they started using substances; it is usually not pain progressing into SUD, a common misconception. It’s important to remember that SUD per se is not usually that physically disabling—not as disabling as psychiatric disorders are. But if there is pain present, the functional decline is profound.

CATR: How should we screen for and talk about pain with patients?
Dr. Manhapra: The key thing is to not get too tied up on pain, and instead to focus on function. If the patient reports pain, decide whether it’s acute (less than 3 months in duration) or chronic pain. The clinical definition of chronic pain is 3 months of pain, almost every day or every day. The CDC guidelines suggest that we measure pain severity, how it affects the patient’s emotional life, and how it affects the patient’s functional life, all on a 0–10 scale.

CATR: How do we address function?
Dr. Manhapra: Questionnaires are useful to identify issues early and to chart progress. For example, there is a three-question validated tool called the PEG Pain Screening Tool that gets at this (www.health.gov/hcq/trainings/pathways/assets/pdfs/PEG_scale.pdf). You can also simply ask: “Is the pain stopping you from doing something? Are you able to do things? Are you afraid of doing certain things that are important to you because of pain? Are you able to play with your grandkids?” The idea is that you ask about functions that matter to the patient. If fishing is important for that person, ask, “Is it stopping you from going fishing?” Then, of course, you should ask about daily functions like, “Are you able to take care of yourself? Are you able to brush your teeth or bathe?”

CATR: Are patients with chronic pain and OUD categorically different from those with OUD alone?
Dr. Manhapra: Yes, I believe so. We recently published a paper arguing that people with comorbid OUD and chronic pain may require specific consideration and even diagnostic criteria because they received medication from a provider who deemed it was safe and proper to use, and they used it, and their current circumstances are largely related to adverse effect of medication use. In this paper, we argue for change in clinical practice, opioid policies, and further research (Manhapra A et al, J Gen Intern Med 2020;35(Suppl 3):964–971).

CATR: And you classify this as a different phenomenon from OUD?
Dr. Manhapra: Yes. We have started calling it “complex persistent opioid dependence (CPOD).” Almost everybody who is taking opioids long-term will have dependence. That level of dependence can be adaptive, allowing them to function well. CPOD is when that dependence has progressed to a level where it is compromising their functional life. And if you stop the opioids, they have persistent and worsening pain and disability due to protracted withdrawal syndrome. However, the dependence has not progressed to an OUD or opioid addiction level characterized by loss of control of use or compulsive use. My experience has been that almost every single patient who is on an opioid wants to come off it; it’s just that they are often unable to, so their behaviors may focus on continuation.

CATR: How do the diagnostic criteria differ between OUD and CPOD?
Dr. Manhapra: As seasoned addiction specialists, we find that these patients do not fit the DSM-5 criteria for OUD or the ICD-10 criteria for opioid dependence. So, we have started developing diagnostic criteria for this new condition that exists in the gray area between physiologic dependence and OUD or addiction. I currently use the following diagnostic criteria in my clinical practice:

1. Patients have to be on long-term opioid therapy for at least 1 year currently or in the past


2. Long-term opioid therapy is ineffective (eg, persistent pain and poor functioning)


3. Opioid taper has failed due to worsening pain and function or medical instability


4. Patients have themselves tried (outside of a supervised taper) to stop long-term opioids and had lack of improvement or worsening of pain and function

Patients have to meet criterion 1 and one of the other 3 criteria.

CATR: How do these criteria differ from standard DSM-5 criteria for OUD?
Dr. Manhapra: Unlike in OUD, you cannot use withdrawal and tolerance as criteria for patients on long-term opioid therapy as many of them are expected to have both phenomena. They do not meet the 4 criteria for impaired control because they obtain opioids legitimately through a provider and use them as prescribed. They do not meet the 2 criteria for harmful use as they use responsibly and the use is deemed safe by a provider. They do not meet the social impairment criteria (failure to fulfill roles, activities given up, continued use despite social harms) because they ascribe these criteria to poor pain control and not opioid use. Their explanation is, “Hey, that’s because I have pain. It’s not because my opioid use has gotten out of control.”

CATR: Is there a biological underpinning to CPOD?
Dr. Manhapra: Before there were doctors, before there were diagnostic tools like X-rays or MRI, the body had one technique: force rest, so that the body can move resources to the injury and give it a chance to heal. The ­combination of pain, suffering, and disability is created to change behaviors in response to the threat of physical injury, enabling healing and survival. This brain process gets malfunctional and generates suffering and disability even in the absence of an injury (eg, fibromyalgia) or after the injury is healed (eg, chronic back pain).

CATR: What about the reward system and the role of opioids in that system?
Dr. Manhapra: Remember that relief is not anti-pain (or anti-nociception); relief is generated through a separate process involving the reward system. People think opioids just block the pain. In fact, more importantly, they affect the reward system, which promotes relief, and the larger affective system. This is why opioids are such powerful “pain medications” and not just analgesics. It’s why people who smoke cocaine or drink alcohol get relief even though cocaine and alcohol have minimal analgesic effects. If you are in the field of pain medicine, you see enough people who come in and tell you, “You know I smoke cocaine to control pain. I don’t get high.” People drink alcohol and use any drugs to get relief from pain. That is because the reward system and the relief system are directly affected by this addictive substance, regardless of any analgesic action of that substance.

CATR: Considering this, I’m left wondering how this theory can inform our treatment of patients on long-term opioids when they have acute pain.
Dr. Manhapra: Treat them. It’s uncomplicated. If they are on buprenorphine and methadone for OUD, that’s to deal with their dependence. Don’t see them as pain medications (although they can provide pain relief). If they are on long-term opioids for chronic pain, they may temporarily require a dose increase or rotation to another opioid. Treat acute pain as you would with any other patient. Most people respond to non-opioid regimens. Few require opioids. If using opioids, use them for a short period. Set up the short-term plan ahead of time and explain it clearly. It is also important to understand that patients with any SUD have a higher risk of developing physiologic dependence, misuse, and other adverse effects.

CATR: What if you have a patient you are treating with buprenorphine who develops acute pain?
Dr. Manhapra: These patients should be first treated with non-opioid medications or interventions, to which they might not respond. They might require opioids. Don’t be afraid to simply treat the pain and add short-acting full-agonist opioids. It is not true that buprenorphine blocks the pain relief effect of other opioids—buprenorphine only blocks the euphoric effect of other opioids. If you use buprenorphine for OUD treatment to prevent craving, the buprenorphine (and the methadone, for that matter) has to occupy at least 70%–80% of receptors to manage cravings and block the euphoric effect. That is why we generally shoot for up to 16 mg buprenorphine daily dose, as for most adults this achieves needed levels of receptor occupancy, and generally this leaves other receptors unoccupied. For pain control, you only need 2% receptor occupancy. So for the majority of patients on buprenorphine or methadone for OUD, you are not 100% occupied. There are at least 2% of the receptors open; that is all that’s required for analgesia in pain relief (Greenwald MK et al, Drug Alcohol Depend 2014;144:1–11).

CATR: You mentioned non-pharmacologic approaches. What should addiction clinicians be aware of in that space?
Dr. Manhapra: The target of treatment of chronic pain is always functional improvement. So, the addiction physician should learn simple interventions that they can use to improve function. “Pain management” interventions (medications, procedures, other interventions for controlling pain) should be restricted to short-term use to overcome acute exacerbations. Patients don’t do well if their only plan is “pain management” without any functional improvement interventions.

CATR: What kinds of interventions should we try?
Dr. Manhapra: What I typically do for patients is address fear-avoidance behavior, based on graded exposure in combination with relaxation. Most patients with chronic pain–associated disability have fear-avoidance behaviors, which means that the subconscious mind has picked up a fear of particular activities because it thinks those activities are harmful to the body. The more avoidance of activities due to fear of pain and injury, the more fear, the more pain, and the more avoidance—so it becomes a vicious cycle.

CATR: How do you do this exposure therapy with your patients?
Dr. Manhapra: Like with anxiety treatment, it’s doing graded exposure. So, you start small: Pick a small distance the patient can walk or something else they can do daily that provokes a moderate amount of pain. For example, a patient may be able to walk 50 yards with pain—not without pain (a pain exposure). And you keep on doing it every day, and after 2 weeks it becomes easy to do, not painless. Then push it up a little until it becomes hard again. Then keep on doing it every day and push it up again in 2 weeks when it becomes easy to do. Use a relaxation technique (deep breathing) if the activity becomes too difficult due to overbearing pain. Pace the increase in activity level (graded exposure). This is a very simple intervention, a poor man’s cognitive behavioral therapy for pain.

CATR: Thank you for your time, Dr. Manhapra.