Chronic Pain and Addiction

I spent most of yesterday reading this book. Back when I blogged Jesse Hall’s Handbook of Critical Care, I (joked? remarked?) that, “I think reading a book like this may cause your viewing experience associated with watching medical dramas to change at least marginally”. This book is less universally ‘useful’ (?) in that respect, but if you or someone you know have seen House, well…

As might be inferred from the book title, most chapters in the book deal with the intersection of chronic pain and substance abuse. I say ‘mostly’ because the last two chapters actually don’t talk a lot about the substance abuse part, focusing mostly on the pain treatment part instead (and they don’t even limit the coverage there to chronic pain, although they talk about this as well). It’s the first book published by Karger Publishers that I’ve read, and to people unfamiliar with these publications I should perhaps note that this book is structured and reads pretty much like a standard Springer publication (of which I’ve read more than a few at this point) – if there’d been no publisher information provided I could easily have mistaken this for a Springer publication. This is not a criticism – I like this book format a lot, although it does often mean that there’ll occasionally be some coverage overlap across chapters.

Some chapters are not that technical but a few of the others are, and this book is a scientific publication obviously written mainly for doctors working with this kind of stuff on a daily basis (“We sincerely hope the readers of this volume will find it valuable for their understanding of these patients and for their own work on helping their patients back to functional and healthy lives.”). I found most of the book quite readable, and I liked it although it’s not quite up there in the ‘super great’ category either. It’s much closer to 4 stars than 2. Maybe I’m too hard on the book on account of just having read Meston & Buss – I don’t know.

If you’ve read along for a while, you’ll know that I’m one of those (/…would like to be one of those? /…would like to think of myself as one of those people wanting to be one of those?) annoying ‘take personal responsibility for your actions and don’t blame everybody and everything else for your own problems’-kind of guy. I’ve known for a while that when analyzing addictive behaviours there are some factors complicating matters and making application of what might be termed the ‘standard’ approach to how to evaluate implicit decision making protocols and their derived consequences turn out to be a bit more troublesome than it usually is; impaired decision making processes is implicitly part of the pathology here, and the extent to which that impairment, and behavioural responses derived from it, is purely biological has not been perfectly clear to me. It’s more clear now, but this stuff is not simple. The book has not changed my views on some things related to such matters that much; I still believe there’s substantial scope for an afflicted individual to be able to make good decisions which counter addictive behaviours and minimize risk of relapse, and I still believe an individual has substantial influence on which risk factors he or she exposes him/herself to, translating into substantial influence on which addictions are likely to become established, if any (‘if you never start smoking because you know smoking is addictive, you’ll never become addicted to nicotine’). But on the other hand it’s clear that some individuals are far more likely to establish addictive behaviours. I knew this, but one thing I had not given much thought is that many of these individuals may not actually be aware they are at high risk at the point in time where the unfortunate decisions starting the process are made (this is not an observation they make in the book, but rather something I realized while reading it); some people will participate in the normal youth alcohol culture and get drunk often at parties, and ten years later they’ll be fine and have no problems managing alcohol – whereas others may at that point face a substantial risk of ending up dying from liver failure because of a much higher inherent vulnerability combined with later behaviours derived from that inherent vulnerability. You may argue that even despite this inherent uncertainty there’s still substantial scope for an individual to rationally estimate and minimize individual risk, e.g. by taking things like family history or race (‘if you’re a Native American, stay the hell away from alcohol!’) into account when making decisions about which addictive compounds to expose oneself to, or by avoiding classical triggers. It should be noted that increased baseline risk will most often increase vulnerability to more than one addictive substance; faulty brain wiring is probably part of the problem, and avoiding heroin will not stop the brain from being wired the wrong way. They go into a lot of details about how the brain wiring looks like and how specific drugs may affect it, but you don’t need to know all the details about that stuff in order to get that basic point. It should be noted that different addictive compounds act on different receptors in the brain and so have different effects on brain chemistry (and behaviour); which probably means that this kind of strategy may not always work…

While on the one hand it makes sense to tell people who for one reason or another may be at high risk of developing addiction to minimize exposure to specific potentially addictive compounds which may ruin their lives, a different point is also made more than once in the book. That point is that exposure to compounds which some susceptible individuals are at some risk of becoming addicted to will often not lead to addiction in people who are not highly susceptible. This is a potentially important observation in the context of long-term treatment of chronic pain using opioids. Here’s a relevant quote from chapter 3:

“Far too many physicians and other health care professionals have uncritically accepted the false allegation that opiate addiction can be induced by medically appropriate long- term treatment of pain with opiates [186]. This leads to medical malpractice and the ethically unacceptable undertreatment of pain in millions of suffering patients. […]
The truth of the matter is that although some chronic pain patients are at risk for addiction, they are a very small percentage of the total number of chronic pain patients. Reliable evidence exists to support the contention that appropriate medical treatment of pain with opiates does not incur a risk of addiction in the vast majority of pain patients. […]
[The data] has prompted the World Health Organization to issue the following guideline on the treatment of chronic pain: ‘When opioids are used – even at heroic doses – in the appropriate medical control of chronic pain, addiction and drug abuse are not a major concern’ [191].”

Other co-authors agree and also emphasize this point – in chapter 5 the authors note that, “The prevailing literature suggests that the rate of addiction in chronic noncancer pain patients exposed to opioid therapy is relatively low, especially in those patients without significant concomitant psychiatric disorders and personal and family history of addiction.”

However having noted that it should also be observed that, “The topic of chronic pain and addiction is divisive, with proponents of aggressive opiate use arguing that addiction in patients with chronic pain syndromes is relatively rare, while those who push for more conservative use argue that opiates cause disorder in many patients and are relatively ineffective against chronic pain over time. There is some discord among the authors in this volume, in part driven by the focus of their work”.

From my reading of the material presented in the book, I think the ‘it may not work particularly well in the long run, and there are a lot of side-effects’ is a better argument against COT (chronic opioid treatment) than the potential for addiction, certainly if doctors are aware of the risk and take steps (urine drug screening, other screening tools, monitoring) to counter it and use proper risk stratification measures. Much of the discussion in the book incidentally centers around opioid treatment of chronic pain, and in this context another key point is emphasized repeatedly:

“It is very important to realize that addiction and physical dependence are different phenomena with different underlying brain substrates [3]. Physical dependence results from the development of pharmacological tolerance, and manifests itself upon abrupt discontinuation of drug administration (or administration of an antagonist drug). Addiction is a chronic, progressively deteriorating disease characterized by compulsive drug use in the presence of harm to the addict and to the addict’s life. Addiction is commonly described as the ‘disease of the 5 Cs’: continued compulsive drug use despite injurious consequences, coupled with loss of control and persistent drug craving [3].”

In another chapter there are only four C’s: “It is these four ‘Cs’ (adverse consequences, [loss of] control, craving and compulsivity) that are hallmarks in differentiating patients legitimately using their opioids from those who are addicted. In this definition, physical dependence and tolerance are not necessary for making the diagnosis of addiction. Moreover, tolerance and physical dependence are normal responses to prescribed opioids and are not counted as a symptom of addiction.”

Whether or not you actually need five C’s, or you can perhaps do with just four, the main point stands that dependence is not the same thing as addiction. As one author put it elsewhere, “the real clinical problem in addiction is persistent drug craving and relapse. […] it is extremely difficult to overcome the persistent drug cravings that the abstinent addict is left with after having achieved (often with great difficulty) abstinence. This is why acute ‘detoxification’ programs are almost invariably clinical failures in treating drug addiction. Indeed, the failure rate is so high that physicians running such programs may be reasonably said to be engaging in medical malpractice.” (on a related point, see this post by Scott Alexander (section II) – he also covers in that post other points covered in the book).

Dependence aspects relate to one part of the brain, addiction aspects to another; they are separate phenomena and should be kept separate when thinking about these matters: “addiction and physical dependence are different phenomena, the first referable to the forebrain mesolimbic and mesostriatal reward-related and habit-related circuitry, the second referable to neural loci in the vicinity of the midbrain dorsal raphe nucleus and the dorsal mesencephalon. Some drugs are addictive without producing physical dependence; other drugs produce physical dependence without being addictive.”

Here’s a bit more from that part of the book:

“Many drugs (including, but not limited to, antihypertensives, cardiac medications and asthma medications) produce pronounced physical dependence but are not addictive. Some drugs (e.g. cocaine) are highly addicting but produce little or no physical dependence. Furthermore, laboratory animals will avidly self-administer addictive drugs in the absence of tolerance, physical dependence or withdrawal discomfort [1, 3]. Indeed, laboratory animals will avidly self-administer addictive drugs in the absence of any prior drug exposure whatsoever, rendering the issue of self-administration due to physical dependence moot. The importance of this fact can hardly be overstated as it unambiguously shows that drug- taking behavior cannot simply be explained by the ability of addictive drugs to ameliorate the withdrawal discomfort associated with abstinence from prior administration of such drugs [1, 3]. Critically, the brain sites mediating volitional drug self- administration are different from those mediating the development and expression of physical dependence.” […]

The quote brings up an interesting point: When exposed to addictive substances, many other species behave just the same way humans do – and in point of fact “it is relatively easy to selectively breed laboratory animals for the behavioral phenotype of drug- seeking behavior (the behavioral phenotype breeds true after about 15 generations in laboratory rodents).” A bit more on that aspect:

“All addictive drugs are subjectively rewarding, reinforcing and pleasurable [1]. Laboratory animals volitionally self- administer them [2], just as humans do. Furthermore, the rank order of appetitiveness in animals parallels the rank order of appetitiveness in humans [2, 3]. Most tellingly, perhaps, all addictive drugs (with the exception of the LSD- like and mescaline-like hallucinogens) activate the reward circuitry of the brain [1, 4, 5], thereby producing the subjective ‘high’ that the drug abuser seeks. Furthermore, the degree of such activation of the brain’s reward circuitry correlates well with the degree of subjective high.”

One way to think about addictive drugs is to think about them partly as substitutes individuals with faulty neurological wiring make use of in order to experience the same joys and pleasures as ‘normal people’ derive from other things such as e.g. sex:

“In 1996, Blum et al. [66, 67] proposed that many aspects of addiction are driven by a chronic basal deficiency in brain reward which mechanistically underlies a chronic basal deficiency in subjective hedonic tone. This hypothesis has been amplified and expanded, both by its original proponents and by others [68–71]. The fundamental notion is a simple one: that drug addicts are either born with or acquire a deficiency state in the dopaminergic brain substrates of reward and positive hedonic tone, and turn to addictive drug use to remedy this chronic reward deficiency. Thus, the reward deficiency hypothesis seeks to explain drug addiction as a type of self-medication, ultimately damaging and self-destructive though it may be. […]

Based upon an extensive review of the literature regarding brain reward mechanisms, Wise [96] suggested more than 30 years ago that ‘the dopamine junction [in the nucleus accumbens] represents a synaptic way station for messages signaling the rewarding impact of a variety of normally powerful rewarding events. It seems likely that this synapse lies at a critical junction between the branches of the sensory pathways which carry signals of the intensity, duration, and quality of the stimulus, and the motivational pathways where these sensory inputs are translated into the hedonic messages we experience as pleasure, euphoria, or “yumminess”’ [96]. While this remains an appropriate description of the role of the reward circuitry in encoding hedonic tone, an extraordinary amount of electrophysiological, neurochemical and behavioral neuroscience research over the last 20 years has made it apparent that the crucial nucleus accumbens reward neurons do more than encode receipt of reward, although encoding receipt of reward is certainly one of their functions [97]. They also appear (1) to encode expectancy of reward [98, 99], amount of reward [98], delay of reward [100], reward delay discounting [101] and errors in reward prediction [102]; (2) to regulate motivation for drug- seeking behavior [103], and (3) to contribute to the synaptic neuroplasticity that underlies the acquisition of addictive behavior patterns [104].”

I think it’s safe to say that “impaired decision making processes is” indeed “part of the pathology”.

The post is already too long, but you can’t really cover all this stuff without bringing up the concept of pseudoaddiction. Not all people who ‘behave as if they’re addicted’ are actually addicted:

“Pseudoaddiction […] describes patient behaviors that occur when pain is inadequately treated, including ‘clock watching’ and ‘drug seeking’. Behaviors such as illicit drug use or deception to obtain opioids could occur in legitimate patients seeking pain relief [76]. Pseudoaddiction can be distinguished from true addiction in that the observed ADRB [Aberrant Drug-Related Behaviors] resolves if pain is adequately treated.”