Improved Treatment for Patients With Long-term Opioid Therapy for Non-cancer Pain in Primary Care (Opi-Prim)
Phase: NA
Conditions: Chronic Pain, Chronic Pain Management, Primary Care
Sponsor: Uppsala County Council, Sweden

  
 
 
 
 
 
 
 
 
 
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CLINICAL TRIAL PROTOCOL 
Improved treatment for patients with long-term opioid therapy for non-cancer pain 
in primary care  
 
 
 
 
Opi-Prim 
 
 
 
Trial Design  
Pragmatic controlled before-and-after study 
 
The following amendment(s) is/are accompanying the protocol: 
1. Date:  
Contact Person (initials):  
2. Date:  
Contact Person (initials):  
 
 
 
 
Trial No: Trial will be registered after feasibility study at 
clinicaltrials.gov 
UCR Project No: 
 
 
  
Sponsor: Region Uppsala, Primary Health Care (Nära vård och hälsa, 
NVH) 
Sponsor Representative: Louise Hamark, Director of Administration NVH 
Co-Sponsor: Uppsala University (UU), Department of Pharmacy 
Co-Sponsor 
Representative: 
 
Mats Karlsson, Head of Department of Pharmacy UU 
 
Coordinating Investigator: Anna Svensson, MD  
Principal Investigator(s): Magnus Peterson, MD, PhD (NVH) 
 
 
 
 
  

  
 
 
 
 
 
 
 
 
 
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Trial number:  
Title of trial: 
Improved treatment for patients with long-term opioid therapy for non-cancer pain in primary care 
Trial ID: Opi-Prim 
Short background/Rationale/Aim: 
The evidence for prescribing opioids to patients suffering from chronic non-cancer pain is weak, and using 
opioids in these circumstances is questionable. Swedish primary health care is responsible for about one-third 
of all first-time opioid prescriptions and has the highest rate of prescription renewals for opioids. The decision 
for long-term opioid therapy (LTOT) should rest on an accurate pain analysis and should result in an 
individualized assessment where the risks of LTOT are set against the impact on quality of life that living 
with long-term pain entails. Multi-professional interventions and a person-centered approach are 
recommended for chronic non-cancer pain. Although pharmacists in primary health care have been 
established internationally with successful examples related to LTOT, their role in Swedish primary care and 
the management of chronic non-cancer pain remains to be studied. Currently, it is unclear which interventions 
are effective in reducing inappropriate LTOT and which alternative interventions are suitable for patients who 
are currently receiving LTOT. The involvement of a care manager in the patient´s care has shown promising 
results regarding quality of care for other long-term conditions, for example depresssion. In Region Uppsala, 
clinical pharmacists havte recently been employed in primary health care, but it is unclear what their tasks and 
responsibilities are and how to best make use of their competence. It is therefore relevant and justified to 
investigate a new person-centered team-based approach including care manager and pharmacist  to optimize 
the management of pain in patients with chronic non-cancer pain in Swedish primary care. This project aims 
to reduce inappropriate LTOT and optimize pain management in patients with LTOT for chronic non-cancer 
pain in primary care through a new person-centered and team-based approach.  
Primary objective:  
To investigate the effects of a new person-centred and team-based approach on pain interference in patients 
with LTOT for chronic non-cancer pain in primary care 
Secondary objectives:  
To investigate the effects of a new person-centred and team-based approach in patients with LTOT for 
chronic non-cancer pain in primary care on secondary endpoints and to perform a process evaluation 
alongside the trial, including a feasibility study. 
Primary endpoint:  
Pain interference measured after 3, 6, and 12 months  
Secondary endpoints:  
Pain intensity, symptoms of depression, symptoms of anxiety, patient satisfaction, health-related quality of 
life, opioid use (morphine equivalents) and symptoms of withdrawal. All secondary endpoints will be 
measured after 3, 6, and 12 months.  
Trial design and setting: 
This study is a controlled before-and-after study that has been designed, and will be reported, according to the 
CONSORT guidelines. Participation will be during 52 weeks (12 months). 
This study will be conducted at eight healthcare centres in Region Uppsala. At four of the healthcare centres, 
a new person-centred team-based treatment model including pharmacists (intervention) will be implemented. 
Prerequisites for these healthcare centres are the accessibility of at least one person of each healthcare 
profession: pharmacist, general practitioner (GP), psychologist (or social worker) and physiotherapist, where 
one of these (or a rehabilitation coordinator or a nurse) takes the role of care manager. Healthcare personnel 
will receive special training in managing patients with chronic pain before the study. In addition, four control 
healthcare centres without a pharmacist will be matched with the intervention healthcare centres according to 
geographic area (urban, suburban, rural), socioeconomical setting and the size of the centres (number of listed 
patients). No specific efforts of implementation will be made in these control centres.  
Prior to the full trial, a feasibility study will be conducted at one intervention centre and one control centre 
with 12 weeks follow-up per participant. 

  
 
 
 
 
 
 
 
 
 
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Trial population:  
Eligible patients in the study are adult (>18 years) patients with their main healthcare contact at one of the 
healthcare centres included in the study, who have received long-term opioid therapy (> 90 days) for chronic 
pain prescribed by a GP during the recent 12 months, according to the primary healthcare quality indicator 
”Lm12alla”. 
Number of subjects: 
Sample size calculations resulted in at least 55 participants per treatment group (110 in total) needed to 
measure a clinically relevant difference in the primary outcome. For the feasibility study, 5-10 participants 
per treatment group will be included. 
Inclusion criteria:  
Adult (>18 years) patient, main health care contact at one of the health care centres included in the study, 
received more than the equivalent of 90 days or more prescription of opioids for chronic pain made by GP 
during the recent 12 months, according to the primary healthcare quality indicator: ”Lm12alla”. 
Exclusion criteria:  
No current opioid use, been referred to a pain clinic or something similar during the last 6 months, is not able 
to speak Swedish, and is not able to provide informed consent. 
Intervention: 
Patients with pain > 3 months and treatment with opioids at the intervention healthcare centres who have 
agreed to participate will start their inclusion in the person-centred team-based treatment immediately at the 
index appointment. The intervention will be performed by healthcare personnel (GP, clinical pharmacist, 
physiotherapist and psychologist) who receive two half-days of training in person-centered care and 
managing patients diagnosed with chronic pain, before the study starts. The intervention will then consist of 
three phases. 
Phase 1 (investigation and assessment, week 1-3):  
- 
A medication review focusing on pain, sleep and depression/anxiety disorders according to the Swedish 
National Board of Social Affairs and Health HSLF-FS 2017:37 by a pharmacist.  
- 
A thorough pain analysis by a GP according to existing guidelines including duration of pain, pain 
localization and pain mechanisms.  
- 
A visit to a physiotherapist for evaluation and assessment of possible treatment regarding physical 
exercise/physical activities and related treatments. 
- 
A visit to a psychologist for diagnostics and treatments regarding psychological and social factors. 
- 
A visit to a care manager  
Phase 2 (treatment plan, week 3-4):  
- 
An appointment with all healthcare personnel involved in Phase 1 including the patient where an 
individualized rehabilitation plan is made based on the biopsychosocial model of pain and in accordance 
with the Swedish Medical Products Agency´s treatment recommendations. 
Phase 3 (treatment and follow-up, week 4-24): 
- 
Implementation of the individualized rehabilitation plan.  
- 
Frequent follow-up contacts (1 per 1-3 weeks) by phone with an established contact person, i.e. care 
manager (pharmacist, physiotherapist, psychologist, rehabilitation coordinator or nurse).  
An appointment with all healthcare personnel involved in the rehabilitation plan, 3-4 months after the 
start of phase 2 to update the plan.  
Control: Usual care at one of the control healthcare centres. 

  
 
 
 
 
 
 
 
 
 
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Ethical considerations: 
Ethical considerations have been made. All participants will provide written informed consent prior to trial 
participation. The feasibility study of this trial has received ethical approval from the Swedish Ethical Review 
Authority (registration number 2023-00313-01, date: 2023-04-23). Ethical approval will be sought for the 
final version of the trial protocol before the full trial can be conducted. 
Trial period: 
Feasibility study: Q3 2023 – Q1 2024 
Trial: Q2 2024 - Q4 2026 
 

  
 
 
 
 
 
 
 
 
 
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1 
TABLE OF CONTENTS 
 
PAGE 
1 
TABLE OF CONTENTS ................................................................................................................. 5 
2 
LIST OF ABBREVIATIONS ........................................................................................................... 7 
3 
PROJECT ORGANIZATION .......................................................................................................... 8 
4 
BACKGROUND INFORMATION .................................................................................................. 9 
5 
TRIAL OBJECTIVES ................................................................................................................... 10 
5.1 
PRIMARY OBJECTIVES ..................................................................................................................... 10 
5.2 
SECONDARY OBJECTIVES ................................................................................................................. 10 
6 
TRIAL DESIGN AND SETTING ................................................................................................... 10 
6.1 
TRIAL OUTLINE .............................................................................................................................. 10 
6.2 
SETTING AND SITE SELECTION ........................................................................................................... 10 
6.3 
STAFF TRAINING AND IMPLEMENTATION ............................................................................................ 11 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS ......................................................................... 11 
7.1 
SUBJECT INCLUSION CRITERIA ........................................................................................................... 11 
7.2 
SUBJECT EXCLUSION CRITERIA .......................................................................................................... 11 
7.3 
WITHDRAWAL OF SUBJECTS ............................................................................................................. 12 
7.4 
SCREENING AND RECRUITMENT OF SUBJECTS ....................................................................................... 12 
8 
TREATMENT OF SUBJECTS ....................................................................................................... 12 
8.1 
PHASE 1 (INVESTIGATION AND ASSESSMENT, WEEK 1-3): ...................................................................... 12 
8.2 
PHASE 2 (TREATMENT PLAN, VECKA 3-4): .......................................................................................... 13 
8.3 
PHASE 3 (TREATMENT AND FOLLOW-UP, WEEK 4-24): ......................................................................... 13 
8.4 
CONTROL: USUAL CARE .................................................................................................................. 13 
9 
ENDPOINTS AND OUTCOME MEASURE ASSESSMENT ............................................................. 14 
9.1 
PRIMARY ENDPOINT ....................................................................................................................... 14 
9.2 
SECONDARY ENDPOINTS ................................................................................................................. 14 
10 
PROCESS EVALUATION ............................................................................................................ 14 
10.1 
FEASIBILITY STUDY .................................................................................................................... 14 
10.2 
PROCESS EVALUATION DURING TRIAL ............................................................................................ 15 
11 
TRIAL ASSESSMENTS AND PROCEDURES OVERVIEW ............................................................... 15 
12 
STATISTICS AND DATA MANAGEMENT ................................................................................... 16 
12.1 
DATA MANAGEMENT ................................................................................................................. 16 
12.2 
STATISTICAL ANALYSIS................................................................................................................ 16 
12.2.1 
Analysis Population .................................................................................................... 17 
12.3 
DETERMINATION OF SAMPLE SIZE ................................................................................................. 17 
13 
ETHICS .................................................................................................................................... 17 
13.1 
ETHICAL CONSIDERATIONS .......................................................................................................... 17 
13.2 
SUBJECT INFORMATION AND INFORMED CONSENT ........................................................................... 18 
13.3 
ETHICAL REVIEW OF THE TRIAL ..................................................................................................... 18 
14 
DATA HANDLING AND RECORD KEEPING ................................................................................ 19 

  
 
 
 
 
 
 
 
 
 
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14.1 
CASE REPORT FORMS ................................................................................................................ 19 
15 
INSURANCE ............................................................................................................................. 19 
16 
TRIAL END OR TERMINATION .................................................................................................. 19 
16.1 
END OF TRIAL .......................................................................................................................... 19 
16.2 
CRITERIA FOR TERMINATION OF THE TRIAL ..................................................................................... 19 
17 
REFERENCES ............................................................................................................................ 19 
18 
APPENDICES ............................................................................................................................ 22 
 
CASE REPORT FORM: ........................................................................ FOUT! BLADWIJZER NIET GEDEFINIEERD. 
18.1 
PRIMARY AND SECONDARY ENDPOINT FORMS .............................. FOUT! BLADWIJZER NIET GEDEFINIEERD. 
18.2 
DATA MANAGEMENT PLAN ..................................................... FOUT! BLADWIJZER NIET GEDEFINIEERD. 
 
 
 

  
 
 
 
 
 
 
 
 
 
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2 
LIST OF ABBREVIATIONS 
List the abbreviations used in the protocol. At first appearance in the text, the 
abbreviated term should be spelled out and the abbreviation should be indicated in 
parentheses. Define the specialised or unusual terms used in the protocol. 
 
AE 
Adverse Event 
ASR 
 
Annual Safety Report (replacing the previous DSUR) 
CRF 
Case Report Form 
CTR 
EU Regulation 536/2014, also called CTR, Clinical Trials 
Regulation 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation 
SAE 
Serious Adverse Event 
SmPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
 
 
 
 

  
 
 
 
 
 
 
 
 
 
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3 
PROJECT ORGANIZATION 
This project is a collaboration between Region Uppsala, Primary Health Care (Nära 
vård och hälsa, NVH) and Uppsala University (UU) for which a collaborative 
agreement has been signed. The project organization is managed by a research group 
consisting of researchers and clinicians affiliated to either one of or both 
organizations, see below. A patient council for the study has been formed, consisting 
of patient representatives from three patient organizations. The patient council is 
regularly updated about the project plans and provides advice and proposals to the 
plans. The research group then needs to follow the patient council’s advice or 
proposals, or explain why the advice/proposal are not being followed. The clinical 
trial or intervention study itself will be performed within NVH. UCR provides project 
planning and data management support and advice to the project organization. UCR is 
also planned to be involved in the statistical analysis (both planning and conducting). 
Research group 
Magnus Peterson, PI NVH 
Anna Svensson, Coordinating investigator 
NVH 
Sofia Kälvemark Sporrong, UU 
Thomas Kempen, UU 
Hanna Ljungvall, UU 
Lena Katila, UU 
Johanna Hellström, NVH 
Patient Council 
The Patient Council consists of members of 
the Fibromyalgia association in Uppland (part 
of the Swedish Fibromyalgia association; 
Fibromyalgiföreningen), Rheumatism district 
Uppsala län (part of the Swedish Rheumatism 
Federation; Reumatikerförbundet) and the 
Swedish Endometriosis association 
(Endometriosföreningen). The representatives 
are: 
Elisabet Andersson 
Birgith Eklund 
Annika Gunnarsson 
Ewa Larsson 
Anna Röjmarker 
Marielle Sandstedt 
 
 

  
 
 
 
 
 
 
 
 
 
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4 
BACKGROUND INFORMATION 
 
Opioids are crucial for treatment of severe acute pain, during surgery, after trauma or 
when treating cancer related pain(1,2). However, the evidence for good pain relief for 
patients suffering from chronic non-cancer-pain is weak and using opioids during 
these circumstances is questionable(1,3,4). Although the opioid-prescription in 
Sweden is not anywhere near that in North America, there has in Sweden in recent 
years, been a shift from weak opioids (e.g. tramadol) to stronger opioids (e.g. 
oxycodone)(2,2,5). Furthermore, primary health care in Sweden is responsible for 
about one third of all first-time opioid prescriptions and has the highest rate of 
prescription renewals for opioids(2). There are indications of patients in primary 
health care, for which opioid prescriptions are renewed even though the indication for 
opioid treatment is doubtful, where a plan for the dose and duration of opioid 
prescription is missing and with multiple prescribers for their opioids.  
 
The decision for long-term opioid therapy (LTOT) should rest on an accurate pain 
analysis based on the biopsychosocial model and should result in an individualized 
assessment where risks of LTOT are set against the impact on quality of life the living 
with long-term pain entails(3–11). Multi-professional and person-centred 
interventions are recommended for chronic non-cancer pain(7). However, opioid 
therapy may reduce patient motivation for such interventions(12–14). Currently, it is 
unclear which interventions are effective in reducing inappropriate LTOT and which 
alternative interventions are suitable for patients that are currently receiving 
LTOT(15).  International research shows that active tapering of opioids with team-
based interventions can be implemented successfully (8,12,16), but forms for 
implementing this in outpatient care in Sweden need to be developed and evaluated. 
 
Clinical pharmacists in primary health care have been established internationally, for 
example in the UK, but are so far uncommon in the Swedish primary health care 
system(17). There are many international examples of successful collaboration with 
clinical pharmacists to reduce LTOT among patients suffering from chronic pain but 
their role in Swedish primary care and the management of chronic non-cancer pain 
remains to be studied(17). In Region Uppsala, clinical pharmacists have recently been 
employed in primary health care, but it is unclear what their tasks and responsibilities 
are and how to best make use of their competence. This provides an opportunity to 
investigate their potential role in reducing inappropriate LTOT in Swedish primary 
health care. 
 
Primary healthcare providers in Region Uppsala are referred to the document “Pain- 
chronic pain, systematic investigation Primary health care” (18)which is based on 
national assessment and treatment guidelines.  
How these guidelines are implemented in primary health care is unclear. Preparatory 
studies to this project show a lack of routines for person-centred and team-based work 
as well as lack of routines of opioid tapering, and suggests that patients treated with 
opioids appear to be excluded from multi-professional care. The GPs in our 
preparatory interview study signalled that patients treated with opioids would need 

  
 
 
 
 
 
 
 
 
 
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more extensive care to taper their medication. The pharmacists in the focus group 
interviews reported a desire to be more involved in the clinical work in general and 
opioid treatment in particular in patients with chronic pain. Other healthcare personnel 
at the healthcare centres requested more insight into each other´s work and improved 
teamwork. It is therefore relevant and justified to investigate a new person-centred 
team-based approach that includes pharmacist involvement to optimize the 
management of pain in patients with chronic non-cancer pain in Swedish primary 
care. 
5 
TRIAL OBJECTIVES 
The overall aim of this project is to reduce inappropriate LTOT and to optimize pain 
management in patients with LTOT for chronic non-cancer pain in primary care 
through a new person-centred and team-based approach. 
5.1 
PRIMARY OBJECTIVES 
The primary objective is to investigate the effects of a new person-centred and team-
based approach on pain interference in patients with LTOT for chronic non-cancer 
pain in primary care. 
5.2 
SECONDARY OBJECTIVES 
The secondary objective is to investigate the effects of a new person-centred and 
team-based approach in patients with LTOT for chronic non-cancer pain in primary 
care on secondary endpoints and to perform a process evaluation alongside the trial, 
including exploring the feasibility of the study design. 
6 
TRIAL DESIGN AND SETTING 
6.1 
TRIAL OUTLINE 
The trial is a controlled before-and-after study that has been designed, and will be 
reported, according to the applicable CONSORT guidelines (19). No randomization 
or blinding will be involved. A feasibility study will be conducted prior to the full 
trial. 
6.2 
SETTING AND SITE SELECTION 
This study will be conducted at eight healthcare centres in Region Uppsala, NVH. At 
four of the healthcare centres a new person-centred team-based treatment model 
including pharmacists (intervention) will be implemented. Basic conditions for these 
healthcare centres are the accessibility of at least one person of each healthcare 
profession: pharmacist, GP, psychologist and physiotherapist, where one of these (or a 
rehabilitation coordinator or a nurse) takes the role of care manager. Healthcare 
personnel will receive special training in person-centered care and managing patients 
diagnosed with chronic pain before the study. In addition, four control healthcare 
centres without a pharmacist will be matched with the intervention healthcare centres 

  
 
 
 
 
 
 
 
 
 
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according to according to geographic area (urban, suburban, or rural) and the size of 
the centres (number of listed patients). No specific efforts for implementation will be 
made in these control centres.  
 
Patients being participants at the intervention health care centres will start their 
inclusion in the new person-centred team-based treatment immediately at the index 
appointment and up to 24 weeks. Participants at the control centres will receive usual 
care. 
6.3 
STAFF TRAINING AND IMPLEMENTATION 
All personnel involved in the study (GPs, physiotherapists, psychologists (or social 
workers), pharmacists including the care manager) will participate in two half day-
sessions of training. In addition to the two half-day sessions, the care managers (i.e. 
one in the team above, a rehabilitation coordinator or a nurse) will receive 
additionally two hours of training in providing person-centred and team-based care. 
The education focuses on optimized diagnostics and treatment of pain according to 
the biopsychosocial model including pharmacological aspects. The training includes 
interactive and case-based lectures on chronic pain, opioids, person-centred care and 
teamwork. The training will be held locally at each healthcare centre and be arranged 
by persons from the research group in collaboration with a psychologist and a 
physiotherapist from the Pain Clinic, Uppsala Academic Hospital. Further, the 
training will include information about the study. To ensure an adequate pain analysis 
the personnel involved will also receive instructions about how to document relevant 
findings in the patients´ electronic health recordings. To avoid duplication of work 
and overlaps at the various care visits, checklists will be created for each profession 
respectively, to result in coordinated documentation.   
It is the responsibility of the investigators to ensure that all personnel involved in the 
trial are fully informed of all relevant aspects of the trial, including detailed 
knowledge of and training in all procedures to be followed.  
7 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1 
SUBJECT INCLUSION CRITERIA 
Eligible patients in the study are adult (>18 years) patients with their main healthcare 
contact at one of the healthcare centres included in the study who have received the 
equivalent of 90 days or more prescription of opioids for chronic pain made by GP 
during the recent 12 months, according to the primary healthcare quality indicator 
”Lm12alla” (20), and provided written informed consent to participate.  
7.2 
SUBJECT EXCLUSION CRITERIA 
Patients will be excluded if:  
- 
They have been referred to a pain clinic (either at hospital or multimodal 
rehabilitation in primary care) within the last 6 months 

  
 
 
 
 
 
 
 
 
 
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- 
They have no current opioid use, severe cognitive dysfunction, e.g., suicidal 
ideation, psychotic symptoms, or dementia, that prevents informed consent.  
- 
They use their opioids for cancer pain 
7.3 
 WITHDRAWAL OF SUBJECTS 
Subjects have the right to withdraw from the trial at any time without prejudice to 
future treatment. In addition, the subject may be withdrawn at the investigator’s 
discretion at any time if it is in the subject’s best interest. In the event that the subject 
drops out or withdraws from the trial, the reason for study discontinuation will be 
recorded in the CRF. 
Reasonable efforts should be made to contact any subject lost to follow-up after end 
of treatment in order to complete assessments and retrieve any outstanding data.  
 
Specific criteria for withdrawal are:  
• Subject’s decision  
• Investigator's discretion  
• Subject lost to follow-up/non-attendance  
• Intercurrent illness 
7.4 
SCREENING AND RECRUITMENT OF SUBJECTS 
Patients with prescription of opioids will be identified based upon a register of 
primary health care indicator: “Lm12alla”(20). The list of possible subjects will be 
randomized and 10 at a time will be contacted, informed about the study and asked 
about participation via 1177 and a letter and, if no answer, by phone after a few days.  
Patients fulfilling the criterions of inclusion will be informed by phone and those who 
express interest in participating will be invited to a first visit at the health care center 
(index appointment).  
 
The following information will be recorded in the participant’s electronic health 
record (Cosmic): Trial name, date when signed informed consent was obtained, PI's 
contact information. 
 
8 
TREATMENT OF SUBJECTS 
8.1 
PHASE 1 (INVESTIGATION AND ASSESSMENT, WEEK 1-3):  
- A medication review focusing on pain, sleep and depression/anxiety disorders 
according to the Swedish National Board of Social Affairs and Health HSLF-FS 
2017:37 will be implemented by a pharmacist (21). This includes patient 
consultation to reconcile what medications the patient is using and has used 
before in relation to pain, sleep and depression/anxiety, and to identify potential 
drug-related problems (non-compliance, side effects, interactions, etc.).  
- A thorough pain analysis is conducted by a GP according to existing guidelines 
including duration of pain, pain localization and pain mechanisms (4).  

  
 
 
 
 
 
 
 
 
 
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- A visit to a physiotherapist for evaluation and assessment of possible treatment 
regarding physical exercise/physical activities and related treatments. 
- A visit to a psychologist for diagnostics and treatments regarding psychological 
and social factors. 
- A person-centred approach is adopted in all patient consultations. In person-centred 
care the patient narrative is essential to invite the patient to a partnership including the 
person, not only the disease but how the disease affects the individuals’ life as a 
whole. Decision on a rehabilitation plane should rest on a partnership between the 
person and health care, which includes sharing of information and a shared decision-
making about treatment. To ensure a safe partnership, the patient´s narrative but also 
the responsibilities of both parties (patient and health care) as well as the 
rehabilitation plane is documented and transparent for all parts(22).  
 
Phase 2 (treatment plan, vecka 3-4):  
 
- 
An appointment with all healthcare personnel involved in Phase 1 including 
the patient where an individualized rehabilitation plan is set up based on the 
biopsychosocial model of pain and in accordance with treatment 
recommendations in the national clinical knowledge support, including aims, 
interventions and a follow-up plan (4,23). The rehabilitation plan will be based 
on the patient´s needs and conditions (e.g., a plan of opioid tapering including 
follow-up by the pharmacist) and documented in the participant´s electronic 
health record by the care manager. The rehabilitation plan will be available to 
the participant through the electronic health record or printed out, based on 
what is suitable for the participant. 
 
8.2 
PHASE 3 (TREATMENT AND FOLLOW-UP, WEEK 4-24): 
- Implementation of the individualized rehabilitation plan.  
- Frequent follow-up contacts (1 per 1-3 weeks) by phone with an established care 
manager, i.e. contact person (one of the team staff or a rehabilitation coordinator 
or a nurse) with a person-centred approach. The care manager´s responsibility 
will be to ensure that health services meet their commitments in the care plan and 
to serve as a main point of contact between participants and health care. 
- An appointment with all health care personnel involved in the rehabilitation plan, 
3-4 months after the start of phase 2 to update the plan.  
8.3 
CONTROL: USUAL CARE 
Participants in the control healthcare centres will receive usual care. This may include 
appointments and treatment by a GP, nurse, physiotherapist and/or psychologist. No 
pharmacist will be working at the healthcare centre. However, NVH does provide 
centralized medication review services to all primary healthcare centres in Region 
Uppsala. Any healthcare professional may request a medication review by a 
pharmacist on a work-from-home basis as part of usual care. 

  
 
 
 
 
 
 
 
 
 
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9 
ENDPOINTS AND OUTCOME MEASURE ASSESSMENT 
9.1 
PRIMARY ENDPOINT 
Pain interference as measured with the Brief Pain Inventory – Short Form (BPI-
SF)(24), question number 9 a-g. The primary outcome measure will be the difference 
in pain interference after 3, 6 and 12 months. A text message will be sent one week in 
advance to the digital link, and in case of missing data, a telephone call will be made 
as a reminder  
9.2 
SECONDARY ENDPOINTS 
Secondary endpoints will be pain intensity (as measured with BPI-SF, question 
number 3-8), symptoms of depression (Patient Health Questionnaire-9; PHQ-9), 
symptoms of anxiety (General Anxiety disorder-7; GAD-7), patient satisfaction 
(Patients´ Global impression of Change; PGIC), quality of life (EQ-5D-5L), opioid 
use (morphine equivalents) and symptoms of withdrawal (Short Opioid Withdrawal 
Scale; SOWS). All outcomes in the intervention study are based on internationally 
recognized IMMPACT-guidelines(25). Secondary endpoints will be measured after 3, 
6 and 12 months, including pain interference at these time points.  
 
10 
PROCESS EVALUATION 
10.1 
FEASIBILITY STUDY 
The aim with the process evaluation unlike the feasibility is to explore the process and 
not only the feasibility. If the process is performed as planned, why the process works 
or not and in which context. What can improve to get a more optimized intervention.  
Factors related to the implementation of the intervention will be investigated. This 
will include individual interviews with all patients and one semi-structured follow-up 
focus groups with health care staff. Questions about the participants´ experience, 
success factors, barriers and suggestions for improvement are made by the 
researchers, which are then reported in text and tabular form. To examine the process 
during the intervention, semi-structured observations will be carried out for all care 
visits. Person-centred and team-based care are two factors to observe during the study. 
The result will be presented in text and tabular form. Patient recruitment data, 
completed intervention components data in term of fidelity, adaption, dose, reach and 
strength will be presented with descriptive statistics. The number and reasons for drop 
outs will be reported and analyzed descriptively. An expected duration of patient 
recruitment for the intervention 
 study will be calculated based on the feasibility. Based on the above results, the study 
protocol for the planned intervention study will be updated.  
 

  
 
 
 
 
 
 
 
 
 
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10.2 
PROCESS EVALUATION DURING TRIAL 
Similar to the feasibility study data collection and analysis above, a process 
evaluation according to the British Medical Research Council framework will be 
conducted to analyse implementation, protocol adherence and participants' experience 
and opinions(26,27) . The process evaluation includes evaluation of the training from 
the perspective of the healthcare staff in questionnaire and interview form. 
Furthermore, a continuous follow-up of the three phases of the intervention will be 
done, above all if and when they are carried out (protocol adherence) and how they 
work by performing observations. In addition, questionaries’ and focus groups, or 
semi-structured interviews, will be held with the healthcare staff who carried out the 
intervention, as well as the operations manager at the participating healthcare centres. 
This is to identify success factors and areas for development. A heterogeneous sample 
of patients will be interviewed within one month of undergoing the intervention. 
These interviews deal with the patients' experiences of the intervention, as well as 
their suggestions for further development and implementation of the intervention. The 
process evaluation will be analysed descriptively and through qualitative content 
analysis as above. The process evaluation for the trial may come and change after the 
feasibility study.  
 
11 
TRIAL ASSESSMENTS AND PROCEDURES OVERVIEW 
All trial assessments and procedures are viewed in Figure 1. 
Time (months) 
Index (0) 
1,5 
3 
6 
12 
Inclusion: 
 
 
 
 
 
Screening in- and exclusion criteria 
X 
 
 
 
 
Informed consent  
X 
 
 
 
 
Interventions: 
 
 
 
 
 
Intervention: phase 1-3 
 
 
 
 
 
Control: usual care 
 
 
 
 
 
Data collection (intervention study): 
 
 
 
 
 
Baseline characteristics  
X 
 
 
 
 
Pain interference (BPI-SF) 
X 
 
X 
(X)* 
(X)* 
Pain intensity (BPI-SF) 
X 
 
X 
(X)* 
(X)* 
Symptoms of depression (PHQ-9) 
X 
 
X 
(X)* 
(X)* 
Symptoms of anxiety (GAD-7) 
X 
 
X 
(X)* 
(X)* 
Patient satisfaction (PGIC) 
 
 
X 
(X)* 
(X)* 
Quality of life (EQ-5D-5L) 
X 
 
X 
(X)* 
(X)* 

  
 
 
 
 
 
 
 
 
 
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16(22) 
Figure 1. Schedule for inclusion, interventions and data collection according to the SPIRIT statement. 
* Study participants in the feasibility study will possibly be asked to be part of the later intervention 
study where follow-up also takes place after 6, 9 and 12 months. This requires new informed consent 
from the study participant. BPI-SF = Brief Pain Inventory - Short form; EQ-5D-5L = EuroQol 5-
dimension 5-level version; GAD-7 = General Anxiety Disorder-7; PGIC = Patients' Global Impression 
of Change; PHQ-9 = Patient Health Questionnaire-9; SOWS = Short Opiate Withdrawal Scale. 
 
12 
STATISTICS AND DATA MANAGEMENT 
12.1 
DATA MANAGEMENT 
Data management will be handled as described in separate Data Management Plan 
 
12.2 
STATISTICAL ANALYSIS 
Primarily, statistical analyses will be conducted based on intention-to-treat (ITT) 
principle. Patient characteristics will be presented descriptively per treatment group. 
The average value of pain interference and quality of life in accordance with BPI-SF 
will be calculated and analyzed separately per treatment group. The difference 
between the intervention group and the control group will be analysed through 
regression analysis including the ability to adjust for base line data and other 
covariates. ANOVA for repeated measurements will be used to analyse the average 
differences between the two groups until 12 months. The number of dropouts will be 
reported and analysed descriptively. All randomized study subjects completing the 
whole study period (complete cases) will be analyzed Per Protocol. For a specific 
analysis, study subjects with missing data on any of the variables in the model will be 
excluded from the analysis. Analyses of this population is seen as sensitivity analysis 
to investigate whether conclusions are sensitive to assumptions regarding the pattern 
of missing data. All analyses will be described in a prespecified statistical analysis 
plan (SAP). Significance tests will be two-tailed and a p-value less than 0.5 will be 
interpreted as significant. All statistical analyses are carried out in an SPSS, SAS or 
R. The process evaluation is analysed descriptively as well as through a qualitative 
thematic analysis. 
 
Self Efficacy(PSEQ-2) 
X 
 
X 
(X)* 
(X)* 
Data collection (process evaluation): 
 
 
 
 
 
Process outcomes (intervention fidelity)  
 
X 
X 
(X)* 
(X)* 
Interviews (patients) 
 
 
 
X 
 
Focus group discussion (not all 
participants)  
 
 
 
X 
 
Observation 
 
 
 
 
 

  
 
 
 
 
 
 
 
 
 
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12.2.1 
ANALYSIS POPULATION 
All eligible subjects will be included in the statistical analyses. Statistical analyses 
will be conducted based on intention-to-treat (ITT) principle. 
12.3 
DETERMINATION OF SAMPLE SIZE 
The power calculation (and thus the sample size) is based on the assumption that the 
data are approximately normally distributed. We assume that the patient size in both 
treatment groups will be the same, 1:1. Based on previous studies and unpublished 
data from the U-PAIN cohort we assume that the baseline value (index visit) for the 
primary outcome is 6,0 in both treatment groups. We consider a difference in change 
of 1,0 between the groups at 12 months to be clinically relevant and assume that the 
standard deviation of the change is 1,43. To detect a difference of 1.0 in pain 
interference between the two groups with a power of 90% and a type-1 error of 5%, 
46 participants in each treatment group is required. With regard to dropouts (20%) we 
aim for at least 55 participants per treatment group (110 in total). Based on the current 
patient count calculation (90% power and α = 0.05 to detect a 1.0 difference in the 
primary outcome measure) based on previous studies (16) and data from the U-PAIN 
cohort (28), we aim in the intervention study for at least 55 study participants per 
treatment group (110 in total). 
 
 
13 
ETHICS  
13.1 
ETHICAL CONSIDERATIONS 
The trial will be conducted in accordance with the protocol, applicable regulatory 
requirements and the ethical principles of the Declaration of Helsinki as adopted by 
the 18th World Medical Assembly in Helsinki, Finland, in 1964 and subsequent 
versions. 
The risks of participating in the project are considered low. Treatment and assessment 
of the study participants in the feasibility as well as in the intervention study will 
deviate from current practice and may affect the participant´s physical and 
psychological health. A reduction in opioids may become relevant among some of the 
study participants which may affect them and lead to temporary symptoms of 
abstinence and increased pain. However, it is important to emphasize that treatment 
and assessment will follow current guidelines of chronic pain and current guidelines 
of opioid tapering.  
The participants in the study will be in a position of dependence on the healthcare 
providers. However, this will not significantly deviate to the patient-staff relation in 
usual care. Furthermore, the study participants will be informed both verbally and in 
writing that they may withdraw their participation from the study whenever they want 
and that a withdrawal will not affect the usual care provided.  

  
 
 
 
 
 
 
 
 
 
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The project may lead to improved treatment of chronic pain in primary healthcare. An 
ethical problem may appear if the intervention is effective, but resources are too 
demanding, or that it displaces resources from other patient groups. As in many other 
situations, priorities of healthcare resources must then be made according to resources 
available. 
13.2 
SUBJECT INFORMATION AND INFORMED CONSENT 
It is the responsibility of the Investigator to provide each subject with full and 
adequate verbal and written information about the objectives, procedures and possible 
risks and benefits of the trial. All subjects will be given the opportunity to ask 
questions about the trial and will be given sufficient time to decide whether or not to 
participate in the trial. The written subject information must not be changed without 
prior discussion with the Sponsor. 
The subjects will be notified of their voluntary participation and of their freedom to 
withdraw from the trial at any time and without giving any particular reason. Subjects 
must also be informed that withdrawing from the trial will not affect their future 
medical care, treatment or benefits to which the subject is otherwise entitled.  
The Investigator is responsible for obtaining written Informed Consent from all 
subjects (or their legally acceptable representatives and/or witnesses, where 
applicable) prior to enrolment in the trial.  
The subjects will consent to: 
- 
Participating in the trial. 
- 
Sponsor representatives and regulatory authorities gaining full access to electronic 
health records, to verify the accuracy of the data collected in the trial.  
- 
Recording, collection and processing of data and storing of data in a database. 
 
It should be clearly stated that the data will not identify any subject taking part in the 
trial, in accordance with the Regulation (EU) 2016/679 (General Data Protection 
Regulation, GDPR). 
A copy of the subject information and the Informed Consent form will be given to the 
subject. The Investigator (or the designated representative) who gave the verbal and 
written information to the subject will sign the Informed Consent form. The 
Investigator will file the signed Informed Consent forms in the Investigator’s File for 
possible future audits and inspections.  
13.3 
ETHICAL REVIEW OF THE TRIAL  
The feasibility study of this trial has received ethical approval from the Swedish 
Ethical Review Authority (registration number 2023-00313-01, date: 2023-04-23). 
The final version of the trial protocol and subject information must be approved by 
the Swedish Ethical Review Authority before the full trial can be conducted. 

  
 
 
 
 
 
 
 
 
 
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14 
DATA HANDLING AND RECORD KEEPING 
14.1 
CASE REPORT FORMS  
Case report forms will be completed for each included subject as detailed in the Data 
Management Plan (Appendix XX) The subject’s identity must always remain 
confidential.  
 
 
15 
INSURANCE 
The subjects are insured through the Swedish Social Insurance Agency 
(Försäkringskassan) and the Swedish Patient Insurance (Landstingens Ömsesidiga 
Försäkringsbolag) as part of standard health care. 
 
16 
TRIAL END OR TERMINATION 
16.1 
END OF TRIAL 
The trial ends when the last subject has completed the last follow-up.  
16.2 
CRITERIA FOR TERMINATION OF THE TRIAL 
The Sponsor reserves the right to discontinue the trial prior to inclusion of the 
intended number of subjects, but intends to exercise this right only for valid scientific 
or administrative reasons. After such a decision, all CRFs must be completed as far as 
possible. 
The trial can be prematurely discontinued in the following cases (examples): 
- 
Trial protocol is difficult to cope with. 
- 
Recruitment of eligible subjects is far too low. 
- 
Unacceptable low Investigator, Sponsor or subject compliance. 
- 
Critical change in personnel, administrative or scientific standards at the Sponsor 
or at the trial centre. 
- 
No significant result will be obtained as anticipated. 
 
17 
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18 
APPENDICES 
Include the following optional appendices, if applicable: