FormalPara Key Points

The study assessed the effect of opioid agonist therapy on pain pathways.

High doses of opioids negatively affect both descending pain and central sensitization.

1 Introduction

Opioid use disorder (OUD) affects approximately 40 million people worldwide, with substantial biopsychosocial consequences for individual health as well as socioeconomic effects for the community. Opioid agonist therapy (OAT) is a treatment strategy, targeting the same nervous system receptors as opioids, in a controlled manner, in order to reduce morbidity and mortality associated with OUD [1]. Therefore, pharmacotherapies for OUD are administered as fixed regimens. The two most common agents used to treat OUD are the partial opioid receptor agonist buprenorphine (sometimes in combination with naloxone) and the full opioid receptor agonist methadone; however, extended-release morphine is also used in some settings. In Austria, for example, more than 50% of the patients in the OAT program are treated with extended-release morphine.[2]

It has been previously demonstrated that the initial analgesic effects of opioids can be followed by enduring neuroplastic changes in the peripheral and central nervous systems. This remodeling can lead to paradoxical increased sensitivity to painful stimuli, which is described as opioid-induced hyperalgesia (OIH). It is caused by central sensitization of nociceptive signal transduction pathways in the dorsal horn and dorsal root ganglion [3].

In brief, nociceptive inputs are transmitted from receptors via peripheral nerves and subsequently the spinal cord. A reduction in the excitation threshold of the peripheral nociceptors, e.g. as a result of inflammatory processes, may lead to an increased activation, which is referred to as peripheral sensitization. The signal can also be amplified at spinal cord level or at supraspinal level, i.e. in the thalamus. This process is called central sensitization [4, 5]. Sensitization, on the one hand, is generally understood to be a physiological, adaptive, self-limiting process that aids in the healing of injuries. Persistent sensitization, on the other hand, is maladaptive and greatly accelerates the development of chronic pain [6]. In contrast, a descending pain-inhibiting system can reduce or suppress incoming signals; however, in cases of a reduced function of this system, pain may be perceived even in cases of minimal nociceptive inputs. This is observed for various chronic pain conditions, e.g. fibromyalgia [7].

The description of opioid-induced changes in the pain pathways has largely been confined to experimental trials or analgesia in the perioperative phase. These phenomena have seldom been described in the setting of OAT, and the few existing reports provide no guidance with respect to the effect of varied doses or substances [8,9,10]. Furthermore, changes in other neurophysiological mechanisms such as temporal summation (TS) and conditioned pain modulation (CPM), which have recently gained broad interest in pain research, have not yet been studied in the setting of maintenance OAT.

As measures of dynamic evoked pain, TS and CPM represent a means of quantifying pain modulation capability, i.e. the potency of amplification or inhibition of nociceptive inputs [11]. CPM describes a ‘pain inhibits pain’ paradigm by assessing a pain threshold (e.g. mechanical pain threshold [MPT]) before and after the application of a painful stimuli (hot water immersion). It is regarded as a parameter for the descending inhibitory system [12]. TS describes the ‘wind-up’ effect of repetitive noxious stimuli, e.g. 10-time application of a certain pinprick [13, 14]. Enhanced wind-up has been hypothesized to represent a marker for higher central responsiveness conducted by C fibers [15, 16].

The aim of the present study was to assess alterations of pain pathways among patients receiving OAT and to elucidate the dose-response relationship for common medications used in the treatment of OUD.

2 Methods

2.1 Ethics, Consent and Permissions

The study was designed as a cross-sectional trial. After approval from the Ethics Committee of the Medical University of Graz, participants were recruited from the ‘Interdisciplinary Contact Point for Medical and Psychosocial Addiction Care’ outpatient clinic in Graz, Austria. Patients receiving OAT in this clinic between 1 July 2021 and 30 August 2021 were approached with an opportunity to participate in the study, and those who voluntarily provided written consent were enrolled. There were no exclusion criteria.

Participants were administered a questionnaire comprising demographic information, questions about substance use, and the central sensitization inventory (CSI) in a resealable envelope with an identification number in order to preserve their anonymity. Study staff were not present while these questionnaires were completed by the patients themselves. The CSI is a self-reported outcome measure consisting of 35 brief questions (separated in two parts). Part A of the CSI consists of 25 questions concerning common symptoms of sensitization, yielding a numeric score (0–100) reflecting the likelihood of central sensitization (with a higher score corresponding to a greater degree of symptomatology) [17]. Part B of the CSI assesses whether the patient has been diagnosed with disorders that bear relationship to central sensitization, such as anxiety or depression [17]. As Part B is only descriptive, it was not further included in our analyses.

2.2 Opioid Equivalency

Each participant’s oral morphine milligram equivalent (MME) was calculated from their documented prescribed OAT regimen based on published data [18]. In this study, 180 patients with OAT were switched from methadone, levomethadone, or buprenorphine to slow-release oral morphine. The investigators reported conversion ratios of 1:58 between buprenorphine and extended-release oral morphine, 1:11.8 between methadone and extended-release oral morphine, and 1:17.4 between levomethadone and extended-release oral morphine [18].

2.3 Measurement Parameters

A battery of somatosensory system assessments was performed for each patient, with each test taking place in a consistent order in a secluded, quiet room at an ambient temperature of 20–21 °C, carried out by a single trained female assessor. The test battery included CPM, heat pain intensity (HPI), mechanical detection threshold (MDT), MPT, mechanical pain intensity (MPI), and TS (Fig. 1). These parameters were selected as they are associated with different functions of the pain pathway: heat pain perception is altered in peripheral sensitization [19], mechanical pain parameters and TS are considered as markers of central sensitization [20, 21], and CPM is regarded as a measure of the functionality of the descending inhibitory system [12].

Fig. 1
figure 1

Study design. CSI central sensitization inventory

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2.3.1 Conditioned Pain Modulation

Our study replicated the protocol previously described to measure CPM using hot water immersion [22]. A hot water bath served as the conditioning stimulus, and for habituation the participant’s non-dominant hand was first immersed for 10 s at a temperature of 37 °C. This was followed by immersion of the same hand in another bath heated to 46 °C, for 2 min. The test stimulus was pressure pain tolerance (PPT), which was measured before and at the end of the 46 °C heat exposure using a pressure algometer (Wagner Pain Test FPN, Wagner Instruments, Greenwich, CT, USA) applied over the adductor pollicis brevis muscle of the non-exposed hand. The algometer pressure was gradually increased at a rate of 0.5 kg/s until the individual reported experiencing a sensation of pain. The relative CPM effect was calculated using the following equation (Eq. 1):

$${\text{CPM }} = \, \left[ {\left( {{\text{PPT}}_{{\text{before heat}}} {-}{\text{PPT}}_{{\text{after heat}}} } \right)/{\text{PPT}}_{{\text{before heat}}} } \right] \, \times { 1}00.$$
(1)

2.3.2 Heat Pain Intensity

Participant’s HPI was recorded at the end of the CPM assessment (e.g., upon removal of their hand from the 46 °C water bath after 2 min) using a 100-point visual analog scale (VAS) with which they subjectively graded the intensity of their pain stimulus at the conclusion of the test.

2.3.3 Mechanical Detection Threshold

Each participant’s MDT was measured using von Frey filaments (OptiHair2, MRC Systems GmbH, Heidelberg, Germany), according to the recommendations of the German Research Network for Neuropathic Pain [23]. Twelve logarithmically scaled filaments were applied to participant`s forearms in order of ascending and descending force, ranging from 0.25 to 512 mN. We applied a Limits Method, wherein a geometric mean representing MDT was calculated from the tactile detection thresholds recorded in three independent series of increasing and decreasing stimulus intensities [23].

2.3.4 Mechanical Pain Threshold

The MPT was measured according to the recommendations of the German Research Network for Neuropathic Pain using pinprick stimulators ranging in force from 8 to 512 mN, with a flat contact area of 0.2 mm in diameter (MRC Systems GmbH). As with MDT, a limits method was used comprising the geometric mean of three independent series to approximate a true value for MPT [23].

2.3.5 Mechanical Pain Intensity

Each participant’s MPI was measured using a calibrated clamp (Algopeg, Algopeg Medical Devices, Schmitten, Switzerland) which applied a force of 10 N to the nail fold of the middle finger on the non-dominant hand. After 10 s, patients were asked to score their subjective pain on a VAS scale (0–100) [24].

2.3.6 Wind-Up

Pinprick stimulators with a calibrated force of 256 mN were used to measure the wind-up phenomenon (MRC Systems GmbH). For this assessment, the sensitivity of patient’s skin at the thumb-ball of the non-dominant hand to a single stimulus was compared with sensitivity to a series of 10 stimuli applied at a frequency of 1 Hz (both in an area of 1 cm2) [23]. The repetitive stimulation was applied manually by an investigator, using a metronome calibrated to one beat per second to provide auditory feedback. Participants evaluated both applied stimuli on a VAS scale (0–100). The wind-up ratio was calculated from the proportion of perceived pain intensity resulting from each stimulus (Eq. 2) [23]:

$${\text{WUR }} = {\text{ Perceived Intensity}}_{{{\text{Series}}}} /{\text{ Perceived Intensity}}_{{{\text{Single}}}} .$$
(2)

2.3.7 Norm Values

Our findings were compared with published norm values. The norm values for MDT, MPT, and wind-up ratio were derived from the German Research Network on Neuropathic Pain (DFNS) [25]. In their publication, the authors reported norm values from 180 healthy individuals from 10 centers across Europe. The norm values for the CSI were based on a study by Ohashi et al., who reported a pain-free control group of 85 Japanese individuals [26]. The CPM data were taken from a large Danish study, in which data of 2,199 randomly selected adults were included [27]. Our methodology for assessing the HPI was previously used by Meeus et al., who reported their results of 31 healthy controls [28]. The Algopeg method for assessing MPI was introduced by the group of Ferrari et al., who reported norm values of 90 healthy participants [29]. All norm values are numerically reported in Table 3.

2.4 Statistical Analysis

The a priori sample size calculation was based on an assumption of a correlation of r ≥ 0.3, alpha = 0.05, and beta = 0.1. With these parameters, a sample of 113 patients was shown to be statistically sufficient. Statistical significance was evaluated using Kruskal–Wallis tests or one-way analyses of variance, as appropriate. Categorical data such as sex distribution and co-medication use were examined using Fisher’s exact test, and comparisons of study data to norm values were accomplished using the two-sample t-test. Finally, linear correlations were evaluated using the Pearson correlation coefficient. Statistical analyses were performed using NCSS 2022 statistical software (NCSS, Kaysville, UT, USA).

3 Results

A total of 120 patients undergoing OAT were recruited to participate. Their characteristics are summarized in Table 1. No patients withdrew before the conclusion of the study. The sample consisted of 85 males and 35 females, the majority of whom received morphine (103), or methadone (8), buprenorphine (5), or levomethadone (4). The mean age of participants was 35.9 ± 7.5 years, with a mean height of 176.3 ± 8.4 cm, mean weight of 77.7 ± 18.8 kg, and mean body mass index (BMI) of 29.9 ± 5.1 kg/m2. The mean daily oral MME among all participants was 693 ± 23 mg, and was highest among those receiving morphine OAT (730 ± 226 mg). On average, participants had been receiving OAT in the substitution program for 8.5 ± 6.0 years prior to study recruitment. The proportion of participants taking at least one co-medication was 6.7%.

Table 1 Descriptive overview of study participants (n = 120), including demographic information and details of opioid agonist therapy, alcohol consumption, and current medication, organized by agent used to treat opioid use disorder
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The results of each test in the somatosensory system battery are presented (categorized by OAT medication) in Table 2, and aggregate values for each test are compared with published norms in healthy populations in Table 3. We did not observe a significant difference in test results between patients receiving the four different agents for OAT (p = 0.060–0.464). The average score on the CSI Part A was 27.8 ± 14.0, and 45% of our sample had a score corresponding to at least ‘mild’ central sensitization. This did not differ significantly from norm values derived from a healthy population (28.9 ± 13.5; p = 0.391) [26]. The proportion of patients in our study population reporting at least one related comorbid diagnosis in the CSI Part B was 43.3%, with 15% reporting more than one diagnosis. These included depression (n = 44), migraines or tension headaches (n = 5), neck injury (n = 2), fibromyalgia (n = 1), irritable bowel disease (n = 1), and anxiety or panic attacks (n = 1). No participants reported a history of restless legs syndrome, chronic fatigue syndrome, or temporomandibular disorders (n = 0). The study population did differ significantly from norm values with respect to CPM (−15.3% ± 14.7% vs. 35.9% ± 45.2%), HPI (53.174 ± 24.5 vs. 23.57 ± 17.0), MPT (166.4 ± 132.7 vs. 129.3 ± 95.5), MPI (45.2 ± 20.8 vs. 18 ± 16), and wind-up ratio (1.83 ± 0.96 vs. 2.67 ± 1.94), but not MDT.

Table 2 Results for each test in the somatosensory system assessment battery undertaken by patients receiving opioid agonist therapy, organized by agent used to treat opioid use disorder
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Table 3 Study values from patients receiving opioid agonist therapy for components of the somatosensory system assessment battery in comparison with published norm values (accompanied by their attribution)
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Pearson correlation coefficients comparing observed parameters from each pain test with the MME of their OAT are presented in Table 4. Significant associations were found between MME and CSI (r = 0.2051, p = 0.025), CPM (r = −0.1806, p = 0.048), MPT (r = −0.2778, p = 0.002), and MPI (r = 0.2977, p = 0.001). Scatter plots of these dose-response regression models are presented in Fig. 2, illustrating a positive relationship between MME and both CSI and MPI, and a negative relationship between MME and both CPM and MPT.

Table 4 Pearson correlation coefficient (r) describing the correlation of observed parameters for each somatosensory system test with the oral morphine equivalent dose of patients receiving opioid agonist therapy
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Fig. 2
figure 2

Scatter plots of a central sensitization inventory; b conditioned pain modulation; c mechanical pain threshold; and d mechanical pain intensity assessments (y-axes) arranged by opioid agonist therapy doses (x-axis) in oral morphine equivalence, with regression modeling (black line) to illustrate significant dose-response relationships. Red circles represent buprenorphine, pink squares represent levomethadone, green triangles represent methadone, and blue diamonds represent extended-release morphine

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The manuscript was prepared in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) criteria. Data are available upon reasonable request.

4 Discussion

Our study found that patients receiving OAT exhibit significant alterations in pain perception, CPM, and wind-up, aligning with opioids’ known potential to paradoxically increase nociception in other settings. However, we take care to note that not all hyperalgesia arising during the course of opioid administration is necessarily ‘opioid-induced’. Taking this into account, our study demonstrates a strong association between OAT and changes in the pain pathways.

4.1 Central Sensitization

The International Association for the Study of Pain (IASP) defines central sensitization as an “increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input.” As direct electrophysiological recordings from central nervous system neurons cannot be performed in humans, the objective assessment of central sensitization in clinical practice is very limited. Clinical assessment typically evaluates surrogate parameters using two strategies. The first, quantitative sensory testing, relies on neurophysiological markers. Both mechanical and dynamic parameters, e.g. MPT, MPI, or TS , have long been recognized as pivotal measures of central sensitization [20, 21]. Supporting this, mechanical hyperalgesia has repeatedly been shown to increase in chronic pain conditions and has been proposed as a predictive tool for persistent postoperative pain [30]. The second strategy commonly used to evaluate central sensitization is the assessment of its clinical consequences and comorbidities, and it is this purpose for which the CSI was developed and validated; however, recent scholarship has demonstrated that these two approaches correlate only weakly [31]. When we designed the study, we took special care to integrate both different approaches for assessing central sensitization. Therefore, we included the CSI as a psychometric, self-report questionnaire, and quantitative sensory tests as neurophysiological parameters.

In our study population, we found that pain perception and markers of mechanical hyperalgesia differed significantly from previously published norm values; however, results from the CSI were divergent. Although 45% of participants indicated CSI values corresponding to at least mild central sensitization, the sample mean and norm values did not significantly differ.

4.2 Conditioned Pain Modulation and Wind-Up

Prior research has consistently demonstrated that increases in TS of pain and decreases in CPM are related to increases in clinical pain, in numerous chronic pain syndromes [32]. However, the possibility of impaired pain modulation due to prolonged courses of opioids (e.g., OAT) is seldom addressed, and the existing evidence is in conflict [33, 34]. With respect to OAT, a recent literature review critically noted that no data on CPM or dynamic parameters in this unique population can be found [35]. We showed that both CPM and wind-up are severely altered among patients receiving OAT, in comparison with published norm values.

4.3 Dose-Response Relationship

The prior literature includes only sporadic investigations of the possibility of a dose-response relationship between high-dose opioids and alterations of the somatosensory system. In the context of OAT, these scarce descriptions are limited to case reports [36,37,38]. To the best of our knowledge, our data are the first to demonstrate a dose-response relationship between high-dose opioids and markers of central sensitization in an observational study.

The dose-response relationship of CPM is particularly interesting in light of conflicting literature [34, 39]. Our data illustrate a moderate relationship between CPM and opioid doses in OAT; however, when interpreting our results, it is pivotal to consider the heterogeneity of our study population and the potential influence of variables, such as the timing of OAT intake, which we have neither assessed nor stratified.

4.4 Population

The need for epidemiological data on opioid-related alterations of pain perception and hyperalgesia in special populations has only recently been articulated [40]. Existing clinical knowledge of OIH is largely limited to the perioperative period. Apart from the fact that these studies were mainly conducted with remifentanil, fentanyl, or sufentanil, which are rarely administered beyond the perioperative phase, tissue trauma per se can lead to sensitization and may therefore confound attempts to measure the contribution of opioids to hyperalgesia.

Very few studies have examined OIH in patients receiving protracted opioid therapy for chronic pain. Of these, many are either conducted with relatively low opioid doses or do not address the dose range at all [32, 41, 42]. Furthermore, chronic pain is often accompanied by somatosensory system alterations, which complicate the interpretation of the effect possibly attributable to opioid therapy.

In patients receiving OAT, these confounders are absent. This population also boasts a second important difference—the use of high-dose opioids often well in excess of the doses typically applied for analgesic purposes. Despite these advantages, few reliable studies have explored the effects of opioids on the pain pathways in this population, and those that do have not reported doses comparable with those in our study.

4.5 Substances

4.5.1 Morphine

Previous studies focused on pain pathway changes during OAT were primarily conducted with buprenorphine or methadone. Data pertaining to patients receiving high-dose morphine as OAT could only be extracted from a small number of case reports [3, 43]. Austria is one of the few countries in which extended-release morphine is used for OAT [2], and, in our sample, over three-quarters of patients are receiving this agent. The present study is therefore uniquely positioned to offer the first large-scale observational report on the effect of OAT with extended-release morphine on changes of pain pathways.

When comparing the effects of the various substances used for OAT in our sample, we did not observe significant differences; however, it must be taken into account that some of these are represented by only a small number of patients, limiting statistical power in the comparison.

4.5.2 Co-Medication

Only 8 (6.7%) participants in the study were concurrently taking a medication with the potential to influence the development of hyperalgesia (e.g., ketamine, antidepressants, anticonvulsants, magnesium). With so few patients receiving co-medication, we were unable to demonstrate any significant association with our observed outcome parameters.

4.6 Measurement Parameters

A recent systematic review identified the common lack of assessment of both pain threshold and pain tolerance in patients with chronic opioid exposure [44]. The methodology used to record pain thresholds is fundamentally relevant to the interpretation of the results; this study’s meta-analysis revealed that cold stimuli were commonly used [44]. This fact could be criticized in view of the fact that heat and mechanical pain, but not cold stimuli, are generally regarded as surrogates for peripheral and central sensitization [45], and their application may have superior validity for the detection of hyperalgesia. Thus, our study has explored the effects of high-dose OAT on changes of pain pathways using the former set of measurement parameters.

4.7 Limitations

Although we have identified several strengths of the present study’s design, some limitations exist that effect the interpretability of our results. First, morphine is the predominant substance in our study population, which limits the applicability of our findings to other settings where morphine is not used for this indication. Morphine is however still considered the reference substance among opioids and therefore these results are of high value, especially since no data with comparably high doses exist.

Other OAT substances are less well-represented in the present study. Although we aimed for a sensitivity analysis, the low number of participants with OAT excluding morphine unfortunately rendered it impossible.

Another limitation is that due to the cross-sectional design, the results of our study are unable to make claims regarding changes of pain pathways as a function of time receiving OAT. However, including this longitudinal aspect was not feasible in the present study design, and will be an intriguing component of future research, especially in patients for whom the dose is tapered over time.

The conversion ratios of the different opioids to oral MME was based on a publication in patients receiving OAT for OUD [18]. These data differ from conversion rates used in acute and chronic pain medicine; however, we decided to use these specific ratios as they are the population closest to ours in terms of indication and dosage. The mean MME in their study ranged between 626 and 922 mg/day and was therefore in the range we observed in our sample. We did however not take dosing time points and timing of intake into account. Although OAT is applied as an extended-release formulation, there are relevant circadian changes in plasma concentrations [46]. In our institution, patients take their OAT in the morning, with the testing taking place around midday and therefore presumably at peak level. As we have not specifically assessed the timing, we cannot rule out a temporal effect.

Likewise, we may have not included other potential confounding variables, including information regarding the co-occurrence of various non-opioid substance use disorders. For smoking, for example, an interdependency with pain perception is frequently reported [47]. Assessing data on addictive behavior is however a methodological challenge, with a great chance of misinformation [48]. We have therefore not included these issues in our questionnaire; however, we cannot rule out that these factors are relevant contributors or confounders.

4.8 Clinical Application and Future Directions

Our results contribute to the understanding of pain experience and modulation among patients receiving OAT and may be generalized to other populations receiving high-dose opioids. Previous work has shown that pain management is a major source of morbidity and quality-of-life reductions among patients with OUD. Our results offer a possible avenue of enhancing pain management for these patients, clearly identifying two main contributors to somatosensory system alterations—central sensitization leading to an amplification of nociceptive input, and simultaneous impairment of the descending pain system causing reduced pain inhibition. Taken together, these factors explain how patients receiving high-dose opioids may experience relevant pain from nociceptive signals that are otherwise perceived as relatively benign stimuli. This corresponds to the clinical definition of hyperalgesia and suggests that therapeutic approaches focusing on the mitigation of these hyperalgesic effects and the augmentation of endogenous pain inhibition systems will be useful tools for the optimization of pain management in patients receiving high-dose opioids.

5 Conclusion

The present trial demonstrates the clear effects of OAT on pain pathways. Both central sensitization and descending pain modulation are negatively affected by high doses of opioids, and our data elucidate a moderate dose-response relationship for these phenomena. This study demonstrates these effects in a unique cohort receiving particularly high doses of opioids, including extended-release morphine, which have seldom been reported in the literature.