Drug-opposite neuroadaptation and breakthrough pain

Abstract

It is only through the advent of extended release/long-acting opioids that the concept of breakthrough pain emerged. The concept suggests that if pain emerges through satisfactory analgesia achieved by an extended release/long-acting opioid, then additional dosing with a short-acting opioid is needed. The concept therefore suggests that breakthrough pain is due to inadequate dosing of opioid. A different explanation, that of drug opposite neuroadaptation or tolerance, turns this thinking on its head. Suppose inadequate analgesia while receiving opioids is not due to an inadequate dose, but rather due to the rebound pain of tolerance. As such, the need to increase the dose sets up further need for pain relief by increasing the dose, the hallmark of negative reinforcement. Negative reinforcement, continued use to avoid negative effects (in this case withdrawal pain), then drives the unhappy state of needing higher doses in a futile attempt to relieve the pain created by the drug itself.

Perspective:

This article describes the neurobiological basis for tolerance to opioid analgesics and highlights the ultimate futility of dose increase as a means of overcoming tolerance. The article argues that so called breakthrough pain could equally be withdrawal hyperalgesia demanding a different response.

Summary:

Could neuroadaptation explain breakthrough pain, and what would this mean in terms of optimizing opioid efficacy and reducing risk of dependence on opioids.

Fear of addiction has interfered with opioid treatment of pain for as long as humans have used opioids as drugs. Attempts to control opioid use and availability wax and wane with the tides of opioid epidemics, which inevitably impacts use and availability of opioids for the treatment of pain. By the mid-20th century mechanisms of both opioid addiction and opioid analgesia were beginning to be understood, and made addiction seem a function of tolerance and withdrawal that would not interfere when opioids were used for the treatment of pain. It was hypothesized that pain somehow protected against the development of addiction. So began an era of promotion of opioid use for the treatment of pain that considered tolerance and withdrawal not as contraindications, but as nuisance factors that could easily be overcome. Tolerance could be overcome by dose escalation, while withdrawal could be overcome by slow taper once the opioid was no longer needed.¹ It started with the promotion of opioid treatment for pain due to cancer, which at the time tended to be a rapidly fatal and excruciatingly painful disease. It was in this context that the principle of titrate-to-effect opioid dosing emerged.² On the premise that there was no ceiling dose for opioids since tolerance to most of their side effects (including potentially fatal respiratory depression) developed alongside tolerance to their analgesic effects, it was proposed that doses could and should be escalated to achieve comfort. The pain scale was also introduced at this time and used as the basis for dose titration. It did not take long for the titrate-to-effect principle to be applied more generally to both acute and chronic pain in addition to pain due to cancer.³

A second dosing principle was suggested when extended-release/long-acting (ERLA) opioids were released onto the market starting with MSContin (morphine sulphate extended release) in the 1980s and later OxyContin (oxycodone extended release) in the 1990s. Because these products would not necessarily provide the steady level of analgesia advertised, the phenomenon of breakthrough pain was suggested. Specifically, it was conceptualized that “breakthrough pain” would arise on a background of analgesia from an ERLA opioid that became insufficient.^4–7 The solution was to add a short-acting opioid to the regime to supplement the ERLA opioid as needed. It is not surprising that applying either the titrate-to-effect principle or the breakthrough pain dosing principle would result in open-ended dose escalation, which ultimately proved to be a major problem since much opioid harm resides with high doses.⁸ Dose escalation can be avoided by utilizing non-opioid approaches to treat intermittent pain exacerbations whenever possible.

With the benefit of several decades of further scientific exploration, it is now possible to see that several of the assumptions concerning addiction, pain and opioid mechanisms on which the titrate-to effect principle and the breakthrough pain principle were based, were incorrect. This is largely because tolerance and withdrawal were misunderstood, especially as they apply to the treatment of pain with opioids.

Tolerance, withdrawal and neuroadaptation

Tolerance to opioids is produced by complex neuroadaptations, and may be thought of as neuroadaptation. Simply understood, drug tolerance is the need for a higher dose to achieve the same effect. If tolerance to an opioid develops and is not met with a dose increase, it may be manifest as a characteristic withdrawal syndrome. Withdrawal is therefore intrinsic to tolerance both phenomenologically and biologically. Since tolerance is a conditioned state, tolerance and withdrawal may emerge even without actual drug withdrawal.^9–12 Tolerance and withdrawal can be benign, meaning short-lived and reversible within days, or can be more enduring or protracted and not easily reversed. With longer duration of therapy, enduring and protracted tolerance develops.^13,14 Short-lived reversible tolerance and withdrawal are usually associated with short-term opioid use, whereas protracted adaptations tend to arise with long-term use. Tolerance and withdrawal are critical factors in the development of addiction, yet they can and do arise during the treatment of pain with opioids without necessarily progressing to addiction.¹⁵ However, it has been a mistake to assume that it follows that the tolerance and withdrawal developing during opioid analgesic treatment are benign. In fact, far from being benign, tolerance and withdrawal explain many of the downsides of chronic opioid treatment for pain including loss of efficacy, poor mood, tendency to misuse and difficulty tapering despite poor efficacy. Despite today’s general acceptance of the opioid treatment’s limited efficacy and safety, recent evidence reveals that there are still millions of Americans struggling to discontinue ineffective opioid pain treatment.¹⁶ We propose that the more enduring and protracted form of tolerance is the driving force for such opioid analgesic failure, and we describe the implicated neurobiological mechanisms in detail. Understanding the neuroadaptations behind this treatment failure may go a long way towards preventing and treating what is still a significant problem in pain management.

Distinguishing acute from protracted tolerance and withdrawal

Biologically, the brain reacts as soon as an opioid drug is taken in the form of an adaptive response termed neuroadaptation. However, the early stages (onset) of tolerance may not be apparent clinically. For example, an opioid at standard dose and frequency may provide adequate analgesia for the treatment of acute pain throughout an average course (3 days) without the need for dose escalation. Although acute withdrawal has been observed after a single administrations of an opioid, a clinically manifest withdrawal syndrome would be rare after termination of standard 3-day opioid analgesic therapy. The tendency to develop tolerance and withdrawal increases with dose and duration of therapy as a result of the development of neuroadaptation. A useful way to consider the clinical manifestations of tolerance is to distinguish what we may call acute withdrawal from protracted withdrawal, withdrawal being the clearest manifestation of tolerance (see Table 1). The earliest symptoms will be those listed in Table 1 under Classic Withdrawal, and in the case of short-term opioid use, these will be the likely (if any) manifestations of tolerance. These symptoms persist for only a matter of days after drug withdrawal. With continued use, protracted tolerance may develop which is manifest with additional more enduring symptoms (see Table 1), and engages different and much more complex underlying processes. Importantly, these symptoms may arise not only upon acute drug withdrawal, but throughout and even long after opioid use, reflecting long lasting brain changes. If protracted tolerance develops, acute withdrawal symptoms may still be manifest, but as with short-term use, acute withdrawal symptoms tend to subside within days. Protracted tolerance and withdrawal should be thought of as enduring neuroadaptation, which unlike acute tolerance and withdrawal will not reverse within days or even weeks.

Table 1.

Classic symptoms of DSM-5 opioid withdrawal (often termed physical withdrawal)

• Irritability

• Anxiety

• Fatigue

• Insomnia

• Muscle aches

• Nausea or vomiting

• Diarrhea

• Fever or chills

• Rhinorrhea

• Lacrimation

• Pupillary dilation, piloerection, sweating

• Yawning

• Dysphoric mood

Pain related symptoms of acute and protracted withdrawal

• Hyperkatifeia

• Hyperalgesia

• Hypohedonia/anhedonia

• Malaise

• Anxiety

• Emotional pain

• Alexithymia

• Sleep disturbances

NOTE: Acute withdrawal lasts in the order of 2 weeks. Symptoms that persist after acute withdrawal may be considered protracted withdrawal symptoms. Both acute and protracted withdrawal symptoms may arise even during opioid use since tolerance and withdrawal are context sensitive and subject to conditioning (see text). Note that the bottom section is an expansion of the DSM-5 criterium of dysphoric mood.

Allostasis, opioids as medications, and addiction

Allostasis is the process of adapting to challenges by adjusting bodily systems to meet new demands. While homeostasis is the “ideal” state, allostasis represents a shift in homeostasis to adapt to a change in circumstance without compromising stability.¹² Allostasis theory has been applied not only to stress, pain and other challenges, but also to chronic opioid medication regimens, opioid misuse, and opioid addiction. Responses to drug use are in the opposite direction to the drug’s effects, and are known as opponent process. These are attempts made to restore homeostasis, and such opponent processes begin with the first dose. An allostatic state is proposed to arise over time as greater opponent process responses are needed in the attempt to restore homeostasis in the face of an opioid challenge to the brain, but actually drive allostasis, a change in pain set point.^9,17–19 (Fig. 1) It is well established that neuroadaptive responses to drugs are drug-opposite effects, and this is true for many drugs, not only opioids.^20,21 What is less well understood is that such adaptation is at the root of drug tolerance. While molecular desensitization processes do arise, they are relatively easy to dismiss as not interfering with drug use because they are direct chemical responses that can be overcome relatively quickly by dose escalation or discontinuation.^22,23 Allostatic opponent process adaptations, in contrast, develop and increase steadily over time, have significant learning and cue-related components, and cannot easily be overcome by dose escalation or discontinuation.^24–27 Indeed, such opponent process adaptations are exacerbated by dose escalation.

Fig. 1.

Allostatic change in emotional state associated with transition to drug addiction. Diagram illustrating an extension of Solomon and Corbi’s (1974) opponent-process model of motivation to incorporate the conceptual framework of this paper. Both panels represent the affective response to the presentation of a drug. This diagram represents the initial experience of a drug with no prior drug history, and the a-process represents a positive hedonic or positive mood state, and the b-process represents the negative hedonic of negative mood state. The hedonic state has been argued to be a sum of both an a-process and a b-process. An individual who experiences a positive hedonic mood state from a drug of addiction with sufficient time between re-administering the drug is hypothesized to retain the a-process. In other words, an appropriate counter adaptive opponent-process (b-process) that balances the activational process (a-process) does not lead to an allostatic state. (Bottom) The changes in the hedonic state in an individual with repeated frequent drug use are illustrated that may represent a transition to an allostatic state in the brain reward and stress systems and, by extrapolation, a transition to addiction (see text). Note that the apparent b-process never returns to the original homeostatic level before drug-taking begins again, thus creating a greater and greater allostatic state in the brain reward system. In other words, here the counter adaptive opponent-process (b-process) does not balance the activational process (a- process) but in fact shows a residual hysteresis. While these changes are exaggerated and condensed over time in the present conceptualization, the hypothesis here is that even during post-detoxification, a period of “protracted withdrawal,” the reward and stress systems are still bearing allostatic changes. The following definitions apply: allostasis, the process of achieving stability through change; allostatic state, a state of chronic deviation of the regulatory system from its normal (homeostatic) operating level; allostatic load, the cost to the brain and body of the deviation, accumulating over time, and reflecting in many pathological states and accumulation of damage. The weights illustrated hanging from the figure illustrate allostatic loads but there is not specific temporal sequence by which epigenetics, trauma, psychiatry comorbidity and opioid misuse impact the development of allostasis.

Adapted from: Sterling P and Eyer J, Allostasis: a new paradigm to explain arousal pathology. In Fisher S and Reason J (eds), Handbook of Life Stress, Cognition and Health, John Wiley, New York, 1988, pp. 629–647 and Koob GF and Le Moal M, Neuropsychopharmacology, 2001, 24:97–129.

Opponent process as the driving force of tolerance

Many theorists have proposed that opponent process is the main driving force of tolerance.^{24,25,28–30} Opponent process theory proposes that drug administration sets in motion adaptations that are opposite to the drug’s effects and maintain homeostasis until the drug is withdrawn. Such responses can be conceived as negative emotional responses resulting in an aversive state. This aversive state results in hyperalgesia and hyperkatifeia which incorporates the increased pain, reward deficiency, and altered stress responses that are seen as arising in the withdrawal/negative affect stage of the addiction cycle.¹⁵ Hyperkatifeia is defined as an increase in intensity of the constellation of negative emotional or motivational signs and symptoms of drug withdrawal such as anxiety, irritability and dyphoria.^31–33 Hyperalgesia is also part of the spectrum of counteradaptive opponent processes. Multiple central nervous system mechanisms underlie opponent process and its manifestation as hyperalgesia and hyperkatifeia. Early and reversible mechanisms include a surge in stress hormones and brain stress systems (glucocorticoids,corticotropin releasing factor, and dynorphin) contributing to both hyperkatifeia and hyperalgesia, while central sensitization (increased glutamate at the N-methyl-D-aspartate receptor, upregulation of cyclic adenosine monophosphate and voltage gated calcium channels) contributes prominently to hyperalgesia.^34–38 Over time, as protracted tolerance develops, opponent process shifts into brain regions that mediate both emotional and physical pain such as the nucleus accumbens, amygdala, insula and cingulate, and its mechanisms tend to account for both hyperkatifeia and hyperalgesia. Such mechanisms include dopamine depletion, brain stress neurotransmitter activation, and neuroinflammation.^31,39 Anti-stress system failure is also important, especially as it contributes to hyperkatifeia.

Drug-opposite withdrawal effects return to baseline relatively rapidly after only a few administrations, but after many administrations, homeostasis can only be restored by cessation of opioid use, and withdrawal recovery slows. With still more time, the negative hedonic response persists even while the drug is on board and may persist long after the drug is discontinued.²⁴ There is thus a shift in the hedonic set point, which becomes an allostatic load and drives an aversive (negative) state or allostatic state. (Fig. 2) Hyperalgesia and hyperkatifeia are thus the drivers of negative reinforcement which becomes an important additional source of motivation for continued pain relief and ultimately compulsive drug use.^18,40,41 Acumulating evidence from animals and humans indicates that even as opioid administration produces analgesia, it concurrently sets into motion certain anti-analgesic or hyperalgesic processes.^11,42 Significant evidence shows that during chronic opioid use, counteradaptation and associated hyperalgesia cannot be explained by waning drug levels since they occur at even at maximal drug concentrations.^19,43 Thus, a hyperalgesic state is created that drives opioid taking even while continuing drug use. The traditional response to deterioration of the analgesic efficacy of opioids if attributed to tolerance was to assume one could correct this with dose escalation. But since dose escalations will strengthen counteradaptation, one must now ask if dose escalation is the right response to opioid analgesic deterioration.⁴⁴

Fig. 2.

Opponent Processes from Acute Drug Administration and Acute Withdrawal to Chronic Drug Withdrawal to Sign Reversal (panels A-C) In opponent process theory, many affective control mechanisms in the brain are hypothesized to act as an emotional stabilization system that keeps mood in homeostatic balance. Under this framework use of a rewarding drug (opioid) initially initiates a positive hedonic effect termed the “a process”. This signal triggers an opposing effect termed the “b process”. Panel A represents comparisons of the effects of b processes for initial opioid taking (relatively novel unconditioned stimuli). Panel B represents drug taking that has been frequently repeated to the point of the development of tolerance and dependence (unconditioned stimuli that have been frequently repeated). Panel C represents drug taking that has been repeated sufficiently to produce a sign reversal (drug opposite effects that have motivational processes even while actively taking the drug). The middle trace shows the underlying affective (hedonic) signals of the a process and b process. The top trace shows the a process minus the b process. The strengthening of the b process is assumed to shorten the b process latency, increase its asymptotic value, and lengthen its decay time (panel B). A negative hedonic response eventually develops not only post drug but also during the period when the drug is on board (panel C). Allostasis theory in opioid tolerance. Pain 2021;162:2315–2319. An opponent-process theory of motivation: I. Temporal dynamics of affect. Psychol Rev 1974;18:119–145. A homeostatic and redundancy theory of tolerance to and dependence on narcotic analgesics. In: Wikler A, The Addictive States (series title: Its Research Publications, vol. 46, Williams and Wilkins, Baltimore, 1968, pp 206–225).

(a) With permission from: Ballantyne JC, Koob GF. (b) Figure modified from Solomon RL and Corbit JD. (c) Adapted from Figure XVI.3 Martin, W.R.

Learning and tolerance

In this context, learning in general has long been hypothesized to contribute to the development of tolerance and withdrawal to opioids.^{45, 46} Extensive preclinical work by Siegel and colleagues demonstrated a key role for Pavlovian conditioning in the development of opioid tolerance that is of clinical relevance.^47,48 More specifically, opioid administration was hypothesized to produce disturbances in the body, manifested as analgesic and anti-anxiety effects that occur presumably largely via the brain. Here, the initial drug effects constitute unconditioned stimuli (the a process), which come to elicit what are termed unconditioned responses (the b process) that are opposite to effects of the drug and are an attempt to compensate for the perturbation that is produced by the drug. (Fig. 2) In the case of opioids, conditioned compensatory responses (CCRs) come to be elicited by drug-associated cues through classical conditioning (Pavlovian conditioning process) and thus are also opposite in direction to unconditioned effects of a drug.^47,49 As such, CCRs can contribute to tolerance in the presence of drug and withdrawal in the absence of drug.^25,48 The conditioning of such drug-opposite effects has direct relevance to opioid overdoses, in which changes in the context of drug taking (changes in CCRs) may reduce, even abolish, tolerance and thus heighten the risk of overdose as shown in both animal and human studies.^47,50–53 For example, in case report studies, patients who received opioids for pain relief also have been shown to be at risk of overdose when the route of administration or context changes.^{47,50,51,54–56} Indeed, opioid overdose has been argued to represent not so much an overdose per se but rather a “failure of tolerance”.^57,58

The conditioning of drug-opposite effects also has relevance to the status of patients who receive opioids for the treatment of chronic pain, particularly when using extended-release opioids, which are stipulated to be given round-the-clock thus facilitating neuroadaptation. Indeed, dosing in intervals sufficient to reverse opponent processes is hypothesized to be protective against the development of dependence.⁵⁹ While opioid overdose is a finite and measurable consequence of cue-related changes in tolerance, it is likely that opponent process adaptation to continuously administered drug results in less obvious and less easily measured withdrawal symptoms such as hyperalgesia and hyperkatifeia, which may be constantly subject to cue-related changes in tolerance.^60–62 However, in the case of the symptom of pain, evidence shows that withdrawal-like hyperalgesia persists throughout opioid analgesia treatment.^11,39,42 The same is true for hyperkatifeia which becomes dramatically manifest during withdrawal from continuously administered opioid. Thus, it is clear that tolerance and withdrawal are susceptible to conditioning, learning, and cue-related changes, placing withdrawal on a conceptual knife-edge where fear of withdrawal (learning) strongly motivates continued opioid use.^63–65

Conclusion

In summary, there is no free ride in the brain in the context of continuous opioid treatment of pain.⁶⁶ Attempts to reverse pain with opioid medications ultimately backfire when tolerance develops. Tolerance is a normal attempt of the brain to restore homeostasis via opponent processes. Such opponent processes include down regulation of reward system activity (including endogenous opioid systems) and increased activity of brain stress system activity, both resulting in the sensitization of emotional pain (hyperkatifeia) and pain systems (hyperalgesia) that perpetuate an allostatic break with homeostasis. Such opponent processes also condition to the environment, and such conditioned responses further contribute to the allostatic state that produces tolerance and perpetuates drug seeking. Recognition of the profound role of opponent processes, conditioning, and tolerance have recently been raised in a number of diverse pathological contexts, but achieving acceptance by the medical community of the clinical implications of this tolerance remains a challenge.^33,58,61,67

Most importantly, what does an opponent process/allostasis understanding of tolerance mean when it comes to the medical management of pain? Opioids remain indispensable for the treatment of severe acute pain and pain at the end of life. But treating chronic pain with opioids is different: prolonged continuous opioid use will be met by counteradaptation and futility as pain breaks through because of tolerance. Traditional teaching is that tolerance and withdrawal will not interfere with successful analgesia, and this remains the teaching in multiple textbooks and other educational resources. But this teaching is based on what happens with short-term use. Opponent process effects come to dominate with longer use and higher doses, which provides the conceptual basis for stating that the reason long-term opioids are rarely effective or safe is precisely because of counter regulation (tolerance). Tolerance and its associated withdrawal get in the way of analgesic efficacy and safety. Dose escalation, while possibly achieving a burst of pain relief, worsens this tolerance and ultimately worsens pain relief.⁶⁷ Because of conditioning, changes in tolerance and symptoms of withdrawal can be triggered at any time and are not simply a consequence of dose reduction. Instead of the bliss of pain relief, chronic administration of opioids often becomes the torture of always being on the brink of not enough. While the clinical relevance of opioid induced hyperalgesia (OIH) per se may be debated,^68–70 OIH cannot be unpacked from hyperkatifeia which is of clear clinical significance and an important driver of continued opioid use despite poor therapeutic benefit.^32,71 For many patients who already use opioid analgesics, slow tapering or a switch to buprenorphine can improve both pain and mood. The old dictum of dose escalation to overcome inadequate analgesia must be abandoned other than in acute or other short-term usage settings, such as end-of-life. Advances in our understanding of the biology and neurobiology of counteradaptation and learning in chronic opioid analgesic treatment are greatly needed to allow more informed methods for avoiding or alleviating the pervasive debilitating dependence that is the consequence of chronic opioid use. In addition, perhaps the gap in clinical research could be filled by assessing whether dosing regimens that avoid dose escalation, for example stable-dose pain-contingent regimens, are capable of reducing the tolerance and dependence which tend to develop when using continuous dose regimens.⁷²