The electronic Persistent Pain Outcomes Collaboration (ePPOC) was established in 2013 as an initiative of the Faculty of Pain Medicine of the Australian and New Zealand College of Anaesthetists. This initiative has grown to include data from more than 100 adult and paediatric services across Australia and New Zealand. Since its implementation, ePPOC has enabled standardized routine collection of data from pain clinics across Australia and New Zealand (1, 2). The ePPOC data set provides a valuable data pool for pain research, with data collected from 80 pain services and over 20,000 individuals over almost 10 years (1). The ePPOC questionnaire consists of well-established, internationally recognized pain assessment scales aligned with the biopsychosocial model of pain.

Nicholas et al. published baseline data from ePPOC for patients (n = 13,343) at time of initial presentation to 36 pain clinics across Australia and New Zealand for pain management (3). This population had a mean age of 52.7 years, 58.4% were female, 86.7% were non-indigenous, 69.5% were born in Australia, 98.7% had chronic pain due to non-cancer causes, and 33.3% of participants were unemployed due to pain. For 46.8% of individuals, the duration of their pain was more than 5 years, for 21.4% of participants the triggering event was an injury at work or school, and the back/spine/sacrum was the main pain site for 47.9% of participants.

These data provided a justifiable surrogate baseline for comparison to assess effectiveness of treatments in select patient groups. Further publications emphasize the importance and versatility of ePPOC data as a comparison to assess the effectiveness of treatment in individual pain management centres or in selected subgroups of patients (3, 4).

In this study we utilized the ePPOC data, as intended, to compare the effectiveness of pain management over time in a specific group of long-term chronic non-cancer pain sufferers who have implanted intrathecal (IT) drug delivery systems (IDDS) to administer IT opioids, as part of a comprehensive approach to their pain management (4). Although the ePPOC dataset has a large sample size and uses standardized measures which provide invaluable baseline data, it is important to acknowledge that there may be demographic and clinical differences in the dataset in the current study compared to ePPOC. The ePPOC data allowed comparison of current patient data to a surrogate baseline in the absence of actual historical baseline data for this group. The use of questionnaires which are incorporated in ePPOC, allows standardized, non-invasive quantification of the impact of IT opioids on patients' pain intensity, quality of life and daily functioning.

IDDS are surgically implanted and comprise an intrathecal catheter attached to a subcutaneous, programmable, refillable pump, delivering continuous IT infusion (5). Although the process of IT pump implantation is invasive, the IT route of drug administration may be utilized to achieve enhanced pain relief when traditional routes of administration prove inadequate, due to poor efficacy and/or dose-limiting adverse effects (6).

In line with published international best practice, most patients receiving long term IT medications for pain relief, receive polyanalgesia including some off-label medication use (7). IT adjuvant agents added to IT opioids in the IDDS include clonidine and local anesthetics with baclofen included to treat chronic pain and spasticity (8). This enables a small fraction of the typical systemic analgesic drug doses to be delivered close to spinal cord receptors/ion channels that mediate pain relief, potentially exceeding the efficacy of oral dosing regimens whilst minimizing side effects due to metabolically-derived neuroexcitatory metabolites of the opioid analgesics, morphine and hydromorphone (9). This increases analgesic effects and duration, limits the need to consistently increase dosage, decreases systemic side effects, reduces systemic exposure to analgesic/adjuvant medications and prevents missed dosage or overdosage (10, 11). However, concordant with other dosing routes, analgesic tolerance may still develop and there remains potential for addiction liability (12, 13). Consistent with any surgically inserted medical device there are potential complications related to the implant procedure (14). Other complications include technical IDDS malfunction, IT catheter fracture or migration interrupting IT drug delivery, infection, granuloma formation, particularly at the catheter tip, as well as refilling and programming errors leading to over or under dosing (14).

Nadeau and colleagues (14) noted that in the United States, chronic pain is often undertreated due to preconceptions of health professionals around imminent opioid addiction, often due to limited medical training in chronic pain management. This includes a lack of awareness of the approximately 13-fold variability in opioid dosing, dependent largely on genetic variability in opioid metabolism (14). Side effects of opioids are often concerns for clinicians but these may be eliminated by swapping to alternative opioids (14). Few clinicians are aware that fully adequate treatment of depression can also yield large gains in pain control (15).

Recent studies have reached varied conclusions regarding the efficacy of IT opioids, delivered via implanted pumps, for chronic pain management. Decreases in pain scores were reported in most studies (10, 16–21), but some studies found no change (3, 22). There remains no clear picture of the impact of IT opioids on the biopsychosocial outcomes of these patients and therefore, this study aimed to address this knowledge gap.

This research study was designed to use existing validated, patient-reported outcome measures, utilized in ePPOC to measure pain intensity and pain interference, depression, anxiety and stress, pain catastrophizing and self-efficacy (23).

Our aim was to compare long-term outcomes of IT opioid therapy in patients with chronic non-cancer pain with a surrogate baseline utilizing a large ePPOC data set for patients at the time of initial presentation to 36 pain clinics in Australia and New Zealand. This research had two objectives: firstly, to use questionnaires consistent with ePPOC to document and describe characteristics of a cohort of patients receiving IT opioids via an implanted pump, managed by doctors at a private pain management practice and perform a stratified analysis of this cohort of patients based on demographic characteristics; and secondly, to compare the current patient cohort receiving long term IT opioid delivery with corresponding ePPOC data from a large cohort of patients, at initial presentation to a pain clinic, not receiving intrathecal opioids, who were seeking management for chronic pain across 36 Australian and New Zealand pain clinics. We hypothesized that in the cohort of individuals studied who had chronic non-cancer pain and who were receiving longterm IT opioid/adjuvant analgesic therapy, the IT route of analgesic/adjuvant agent delivery has contributed to positively improved outcomes.

There is increasing awareness of the need for comprehensive evaluation of the chronic pain experience (33). In the context of patients with chronic non-cancer pain receiving longterm IT opioid delivery for pain management, this delivery route has been used when conventional pharmacological treatments, multidisciplinary pain management methods, and/or spinal surgery had not been successful (26). In a broader context, Nadeau and colleagues (15) reported that for patients with chronic cancer pain, physicians in the United States treating chronic pain related to cancer with opioids, appear to be particularly conservative in their use of orally administered opioids, seldom exceeding 300 morphine milligram equivalents daily, and hence a tendency to switch to IT opioid administration even though oral regimens may have sufficed if properly managed (15).

Our study recruited 49 adults, 96% of whom had experienced chronic non-cancer pain for longer than five years. Participants with chronically implanted pumps delivering IT opioids reported significantly lower pain severity, pain interference, anxiety, depression, stress, rumination, magnification, helplessness, and catastrophizing, as well as higher self-efficacy, when compared with approximately 13,000 participants in the ePPOC dataset sample (3) upon entry to 36 pain clinics across Australia and New Zealand. Our study utilised this entry to pain unit data as a surrogate baseline with which to measure change over time with treatment.

The use of ePPOC data from 13,343 patients collected at initial visit to one of 36 pain clinics in Australia and New Zealand as surrogate baseline data for the present study has been useful, but has limitations. The large ePPOC data set does not include details of pain treatments or medication (specifically opioids) prior to initial presentation at a pain clinic. In the period included in the ePPOC data collection (2013–2016), opioid use was widespread in primary practice in Australia. It is likely that all patients in the study group were receiving significant amounts of opioids via systemic routes prior to implantation of the IDDS. Historical baseline data for the patients in the present study would likely have reflected this substantial systemic opioid use.

Our findings suggest that long-term IT administration of opioids for a select group of patients, via a chronically implanted pump, may provide benefit as part of a long-term pain management plan. Our data shown in Figure 1 show considerable inter-patient variability in patient outcomes and this finding may be underpinned by the fact that the two patient populations were at different stages in their pain journeys. Specifically, 96% of our patient group had been in active treatment at the pain facility for longer than 5 years, whereas those that contributed to the Nicholas et al. ePPOC dataset were assessed on their first presentation to a pain clinic (3), although they may have seen multiple different health practitioners prior to being referred to the pain clinic.

In our study, demographic data was similar to previously published groups. A high proportion of participants reported an injury at work as the triggering event for their pain. This is aligned with the findings of Herring et al. (2), where 75% of patients receiving IT opioids for pain relief reported an injury had instigated their pain. Similar to the findings of Schultz et al. (34), a high proportion of current study participants had multiple comorbidities unrelated to their pain condition. Spinal pain back/spine/sacrum was identified as most frequent pain site, concordant with other studies where patients received IT opioids (5, 10, 13, 34–36). Study participants had varying numbers of pain sites consistent with the data reported by Nicholas et al. (3) and data reported by Duarte et al. (35) for patients receiving IT opioids delivered via implanted pumps.

86% of our study participants were taking no or only one oral analgesic, concordant with the findings of three previous studies in patients receiving IT opioids for chronic non-cancer pain management (17, 23, 36). However, research by D'Souza et al. (37) showed opposite findings with an increase in opioid dosage both perioperatively and postoperatively observed in patients with long-term chronic non-cancer pain.

BPI outcomes showed strong relationships between patients receiving IT opioids and decreased pain severity and interference compared with patients on first admission to pain clinics. Participants who qualified for IT opioid pumps can be assumed to have had “severe” pain scores and interference prior to pump insertion. This is consistent with IT opioid delivery devices being reserved as a last resort treatment measure for the most difficult to treat patients with the most recalcitrant pain conditions. Therefore, the lower severity observed in the current study group [2.1 points lower than Nicholas et al.'s sample (3)] indicates that long-term IT opioids, delivered via implanted pumps have contributed to this outcome. These findings are in accordance with Hamza et al. (13) and Duarte et al. (35), who also showed reduced pain severity on BPI scores in patients receiving IT opioids via implanted pumps. Hamza et al. (13) also showed decreased interference comparing baseline data (before pump insertion) to follow-up. Recorded comments by study participants receiving IT opioids via implanted pumps (Supplementary Table S1) on increased work capacity and improved quality of life, are aligned with comments made by participants in other published research (34).

DASS outcomes demonstrate strong correlations between patients receiving IT opioids via implanted pumps, and decreased depression, anxiety and stress consistent with others who showed decreased depression and anxiety in patients with implanted pumps for IT opioid administration (35, 36). However, contrary findings have been reported where no differences in depression, significant stress or mental sum scores were observed when compared with Nicholas et al.'s sample (10). Authors acknowledge observed psychosocial improvements are likely to have been secondary effects due to a reduction in pain, rather than directly attributable to IT drug administration via the IDDS.

Herein, this research is the first to show strong correlations between helplessness and overall catastrophizing, and IT opioid therapy, as well as correlations between rumination and magnification, and IT opioid therapy. Lower catastrophizing scores are associated with positive mental health outcomes, which are vital for individuals coping with chronic pain.

Scores on the PSEQ showed strong correlations between participants with implanted pumps for IT opioid delivery and high self-efficacy, as compared with patients upon first presentation to a pain clinic. Past research has shown that higher self-efficacy is associated with reduced pain (5). Current study results are in accordance with Duarte et al. (35), who found increased self-efficacy in patients receiving IT opioids via implanted pumps when assessed by a multidisciplinary team. Given the importance of self-beliefs on chronic pain outcomes, this finding has importance.

The outcomes of this study provide a comprehensive picture of the chronic pain experience in this special population and the impact of IT opioid therapy on the perception of pain, and supports the benefits of this treatment modality for their ongoing care. However, it is important to note the complications associated with such devices. These include the invasiveness of implantation, the risk of infection, the risk of device failure and the downstream ramifications from these problems (38). Our findings provide an important contribution to the otherwise sparse landscape of literature regarding quality-of-life measures for individuals with chronic non-cancer pain managed by IT opioids delivered via implanted pumps.

The main limitation of this study was the lack of historical baseline data for this legacy patient group, limiting generalizability of the results and correlation of improved outcomes directly with IT opioid therapy. Another limitation of this study was the unbalanced sample sizes of patients with chronically implanted pumps for IT opioid administration (n = 49) and the ePPOC dataset (n = 13,343) published by Nicholas et al. (3). Social desirability may also have impacted findings, with participants potentially giving positive answers to the self-report questions to please research interviewers. Future larger scale multicenter studies would be valuable. Also, the reliance on legacy patients as participants in the IT opioid pump group, had the potential to introduce selection bias and limit generalizability due to the impact of long-term specialist care on pain outcomes. Patients who had previously been treated with IT opioids without success would have been lost from the current patient cohort of legacy patients contributing a bias towards positive outcomes. Potential confounding variables such as the duration of prior treatments and psychological comorbidities were also not recorded as part of this study and may have impacted outcomes. The impact of polypharmacy on pain outcomes is another consideration as many patients included in the study were also taking supplementary analgesics or other medications for co-morbid conditions.

This study demonstrated the utility of the large data ePPOC initiative of the Faculty of Pain Medicine of the Australian and New Zealand College of Anaesthetists. Published ePPOC data has provided justifiable surrogate baseline data allowing opportunities for outcomes research into select patient treatment groups where actual historical baseline data does not exist. This study indicates broader biopsychosocial impacts from IT opioid therapy for chronic non-cancer pain management in a select patient population. This work highlighted the difficulties in conducting research with this legacy patient population due to comorbidities and the lack of historical baseline data for these patients.

Compared with the ePPOC study group upon initial presentation to one of 36 pain clinical in Australia and New Zealand, participants in the present study who received long-term IT opioids reported significantly lower (p ≤ 0.001) pain severity (4.3 vs. 6.4), and pain interference scores (5.5 vs. 7), significantly lower depression (20.2 vs. 13.7), anxiety (9.6 vs. 14.1), stress (15.5 vs. 21), rumination (6.9 vs. 10), magnification (3.8 vs. 5.9), helplessness (9.7 vs. 14.1), general catastrophizing (20.4 vs. 29.8), and higher self-efficacy (29.5 vs. 20.7).

Our present data may assist clinicians considering use of, or currently managing patients with, implanted IT drug delivery devices. It is important to note that the improved outcomes for patients using long-term IT opioids administered via IDDS relative to the surrogate baseline ePPOC data, did so as part of a comprehensive pain management plan. Furthermore, as the process of IT pump implantation is highly invasive, the IT route of drug administration is only used for pain relief when traditional routes of analgesic/adjuvant drug administration prove inadequate due to poor efficacy and/or dose-limiting adverse effects (6).

The stated limitations of this study preclude definitive conclusions regarding improved efficacy of IT opioids, however, there are still important findings to consider. The study results allow suggestion that long term IT opioids may be associated with superior achievable efficacy and/or less side effects than high dose opioids by conventional routes in patients with chronic non-cancer pain that failed to respond to administration of opioids and other analgesic/adjuvant agents delivered by systemic routes. The increased efficacy and reduced systemic side effects can be considered to have contributed to the demonstrated improved outcomes of pain control, function and psychological well-being.

These conclusions are suggested, but not established by this study, and are instead, a basis to support further specific studies on these topics. Future research should consider a randomized clinical trial or pre-post investigation on IT opioid pump management to obtain a more direct comparison.