Chronic PainPhase 4NCT00916890
Prospective Study About Clinical and Pharmacogenetic Safety of Opioid Use for Chronic Pain
A Phase 4 study testing Morphine, Oxycodone and Fentanyl in people with Chronic Pain, run by Fondazione IRCCS Policlinico San Matteo di Pavia at 6 sites in Italy.
Trial summary
Aim of this project is to customize the choice of the strong opioid in the treatment of cancer chronic pain through the identification of patient clinical history and pain characteristics, moreover in the analysis the investigators will also correlate the clinical efficacy and safety of opioid treatment with… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Chronic Pain
- What is being tested?
- Morphine, Oxycodone and Fentanyl
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 320 participants
- Where
- 6 sitesItaly
- Study dates
- Feb 2009to Dec 2015
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Adult oncologic patients (>= 18 years old)
- Chronic peripheral neuropathic and/or nociceptive pain
- Written informed consent
Who cannot join
- Pediatric patients
- Mental impaired patients
- Substance abuse disorder
- Opioid allergy
- History of opioids use or addiction
- Severe immunodeficiency, severe renal impairment, severe liver disease
- Cachectic state
- HIV positive patients
Trial locations and contacts
6 sites in 1 country.
6 sites in 1 country
Italy6 sites
Servizio di Anestesia e Rianimazione e Terapia Antalgica - Ospedale Sant'Orsola-Poliambulanza
Brescia, 25011
Servizio di Anestesia e Rianimazione e Terapia Antalgica - Ospedale Mellino Mellini
Chiari, 25032
Unità operativa di Anestesia e Rianimazione - Azienda Ospedaliera San Gerardo
Monza, 20052
Fondazione IRCCS Policlinico San Matteo
Pavia, Pavia, 27100
Unità operativa di Terapia Antalgica e Cure Palliative - Ospedale Infermi
Rimini, 47900
Struttura Complessa di Medicina Interna - Ospedale Civile di Voghera - Azienda Ospedaliera provincia di Pavia
Voghera, Pavia, 27058
About this study
Official title: Chronic Administration of Opioids in Cancer Chronic Pain:an Open Prospective Study on Efficacy, Safety and Pharmacogenetic Factors Influence.
Aim of this project is to customize the choice of the strong opioid in the treatment of cancer chronic pain through the identification of patient clinical history and pain characteristics, moreover in the analysis the investigators will also correlate the clinical efficacy and safety of opioid treatment with pharmacokinetic and pharmacogenetic patterns in order to identify variables able to predict the efficacy of the treatment or the patient susceptibility towards a specific treatment.
Furthermore with this study the investigators want to identify the pharmacogenomic characterization responsible for pharmacokinetic variability in the conversion between morphine and other opioids, in order to validate the currently available conversion tables from a pharmacokinetic viewpoint, estimating the influence of the most common genetic polymorphisms, and if this characterization could be useful and cost-effective. This study will also focus on the specific clinical-pharmacological response in the elderly and between male and female and on the interactions between opioids and those anticonvulsant and antidepressant drugs routinely used in the pain therapy (study of pharmacovigilance).
Read the detailed description
Pain continues to be a major problem in patients with cancer, affecting 25% to 30% of patients with recently diagnosed cancers. The incidence of pain in advanced stages of cancer approaches 70% to 80%. There are a number of reasons that patients with cancer experience chronic pain either related to the disease itself or to its treatment.
Cancer can spread by metastasis or direct invasion, and 90% of patients with metastasis to osseous structures report pain. Patients with cancer can have neuropathic pain due to direct compression of nerves or plexus or spinal cord involvement.
Inadequate treatment and undertreatment are associated with increased pain scores, decreased functional ability, and increased depression and anxiety.
Opioid administration though proven to be effective still meets with resistance from both healthcare operators, who are seldom willing to prescribe these drugs, and patients, who tend to not take them because of many false beliefs still related to opioids.
It is well demonstrated by the literature that opioids are effective in controlling both acute and chronic pain of nociceptive and/or neuropathic origin. Switching type of opioid and/or administration routes (e.g., from oral to neuraxial) is also known to be an important factor in long-term treatment: appropriate conversion tables elucidating drug equipotence and different potency in base of administration route for the different opioids currently available have therefore been devised and validated in the clinical setting.
There have been several attempts to define guidelines for treatment protocols and even recent meta-analyses indicate that morphine should remain the gold standard. However, a general consensus is still lacking, as opioid management depends not only on the type and cause of pain, but also on the patient's history, the pain characteristics and genetic patterns. Which, if any, is the best opioid, in relation with previous characters, to start systemic treatment remains therefore debated. The different effects that different opioids have on spinal cord sensitization as a result of continuous peripheral nociceptive stimulus in long term administration have also been partially investigated.
Current pharmacogenetic publications analyze the pharmacokinetic behavior of opioids in short-term administration, but studies are still lacking on how the pharmacokinetics and analgesic effect vary after repeated administrations of opioids, especially through direct comparison with clinical response. Genetic studies showed differences in the results of opioid treatment related to the variability of the genes that have a role in the pharmacodynamic and pharmacokinetics of opioids. Regardless these studies, the literature has not yet investigated how quantitative and qualitative variability of gene products can influence the efficacy or the toxicity of a specific opioid treatment.
- Conditions
- Chronic Pain
- Being tested
- Morphine, Oxycodone, Fentanyl, Buprenorphine
- Keywords
- Opioid pharmacogenetics, Opioid pharmacokinetic, Long-term opioid treatment, Cancer pain
- Medical subject headings
- Chronic Pain, Cancer Pain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MorphineDrug
After a titration phase with fast-release oral morphine, once the optimal dosage (no side effects and less than two rescue doses per day) is reached, an equipotent dose of oral sustained-release morphine will be randomly assigned to a patient.
OxycodoneDrug
After a titration phase with fast-release oral morphine, once the optimal dosage (no side effects and less than two rescue doses per day) is reached, an equipotent dose of oral extended-release oxycodone will be randomly assigned to a patient.
FentanylDrug
After a titration phase with fast-release oral morphine, once the optimal dosage (no side effects and less than two rescue doses per day) is reached, an equipotent dosage of transdermal fentanyl will be randomly assigned to a patient.
BuprenorphineDrug
After a titration phase with fast-release oral morphine, once the optimal dosage (no side effects and less than two rescue doses per day) is reached, an equipotent dosage of transdermal buprenorphine will be randomly assigned to a patient.
| Study group | Role | What they receive |
|---|---|---|
| Oral extended-release morphine | Active comparator | Not described Receives: Drug: Morphine |
| Oral extended-release oxycodone | Active comparator | Not described Receives: Drug: Oxycodone |
| Transdermal fentanyl | Active comparator | Not described Receives: Drug: Fentanyl |
| Transdermal buprenorphine | Active comparator | Not described Receives: Drug: Buprenorphine |
What is being measured
The primary outcome is the main question the study is designed to answer.
To identify the drug with the best clinical-pharmacological safety-efficacy profile among the four opioids: oral extended-release morphine, oral extended-release oxycodone, transdermal fentanyl and transdermal buprenorphine.
We will define a treatment effective if it will produce a mean reduction of NRS values at least of 40% than basal values. Among all effective treatments, we will identify the best as the one that will have a reduction of NRS to a value of 4 or less in 90% of patients compared to the 70% of the others treatments. To evaluate pharmacological safety the plasma concentrations of the drugs and their metabolites will be measured. We will branch patients population in 3 groups to evaluate the correlation between clinical-pharmacological response and genetics (responder,partially and not responder)
Measured: 15 days after randomization (Reduction of at least 40% of median daily pain, on a NRS)
Secondary outcomes (1)
Pharmacokinetic of opioids and of their metabolites during long-term administration; correlation between specific genotypes and clinical response or the clinical/pharmacological susceptibility to side-effects on administration of a specific opioid.
Comparison of plasma levels of opioids and of their metabolites in "responder" patients (clinical effectiveness without side effects), "partially responders" patients (clinical effectiveness without side effects but taking not more than 2 rescue doses per day), and in "non responder" patients (3 groups: clinical un-efficacy, side-effects, tolerance and/or opioid induced hyperalgesia).Evaluation of the correlation between the polymorphisms studied and clinical response; the frequency of allelic variants of interest will be compared in "responder", "partially responder" and "non responder".
Measured: 6 months (each patient will be followed for 6 month after enrollment with clinical/pharmacological evaluations once a month and if inefficacy, tolerance or side effects)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Jun 2009 (estimated)
- Study startFeb 2009
- Primary completionFeb 2015 (estimated)
- Study completionDec 2015 (estimated)
Why it stopped: difficulties in patients enrolment
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Chronic PainStudies of the same condition, open and under way.
- More trials run by Fondazione IRCCS Policlinico San Matteo di PaviaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 320 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Fondazione IRCCS Policlinico San Matteo di Pavia
- Sponsor type
- University, hospital or other
- Collaborators
- University of Pavia
- Responsible party
- Principal investigator, Massimo Allegri, Fondazione IRCCS Policlinico San Matteo di Pavia
- Investigators
- Massimo Allegri, MD, Principal investigator, IRCCS Foundation Policlinico "San Matteo", Pavia, Italy
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00916890
- Sponsor's protocol ID
- PT-SM-1-Op-Cancer
- Status last verified
- Jan 2014
- First submitted
- 9 Jun 2009
- Last updated
- 9 Jan 2014
- Results posted
- No
- Data monitoring committee
- No
Publications
De Gregori S, Minella CE, De Gregori M, Tinelli C, Ranzani GN, Govoni S, Allegri M, Regazzi M. Clinical pharmacokinetics of morphine and its metabolites during morphine dose titration for chronic cancer pain. Ther Drug Monit. 2014 Jun;36(3):335-44. doi: 10.1097/FTD.0000000000000009.
PubMed 24595069
Study at a glance
From the registry record, last updated by the sponsor on 9 Jan 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Chronic Administration of Opioids in Cancer Chronic Pain:an Open Prospective Study on Efficacy, Safety and Pharmacogenetic Factors Influence.
- ClinicalTrials.gov ID
- NCT00916890
- Acronym / sponsor ID
- PT-SM-1-Op-Cancer
- Conditions
- Chronic Pain
- Keywords
- Opioid pharmacogenetics, Opioid pharmacokinetic, Long-term opioid treatment, Cancer pain
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- SuspendedReason stopped: difficulties in patients enrolment
- Enrolment
- 320 participants (estimated)
- Lead sponsor
- Fondazione IRCCS Policlinico San Matteo di PaviaUniversity, hospital or other
- Collaborators
- University of Pavia
- Study start
- Feb 2009
- Primary completion
- Feb 2015 (estimated)
- Study completion
- Dec 2015 (estimated)
- First posted
- 10 Jun 2009 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Aim of this project is to customize the choice of the strong opioid in the treatment of cancer chronic pain through the identification of patient clinical history and pain characteristics, moreover in the analysis the investigators will also correlate the clinical efficacy and safety of opioid treatment with pharmacokinetic and pharmacogenetic patterns in order to identify variables able to predict the efficacy of the treatment or the patient susceptibility towards a specific treatment.
Furthermore with this study the investigators want to identify the pharmacogenomic characterization responsible for pharmacokinetic variability in the conversion between morphine and other opioids, in order to validate the currently available conversion tables from a pharmacokinetic viewpoint, estimating the influence of the most common genetic polymorphisms, and if this characterization could be useful and cost-effective. This study will also focus on the specific clinical-pharmacological response in the elderly and between male and female and on the interactions between opioids and those anticonvulsant and antidepressant drugs routinely used in the pain therapy (study of pharmacovigilance).
Detailed description
Pain continues to be a major problem in patients with cancer, affecting 25% to 30% of patients with recently diagnosed cancers. The incidence of pain in advanced stages of cancer approaches 70% to 80%. There are a number of reasons that patients with cancer experience chronic pain either related to the disease itself or to its treatment.
Cancer can spread by metastasis or direct invasion, and 90% of patients with metastasis to osseous structures report pain. Patients with cancer can have neuropathic pain due to direct compression of nerves or plexus or spinal cord involvement.
Inadequate treatment and undertreatment are associated with increased pain scores, decreased functional ability, and increased depression and anxiety.
Opioid administration though proven to be effective still meets with resistance from both healthcare operators, who are seldom willing to prescribe these drugs, and patients, who tend to not take them because of many false beliefs still related to opioids.
It is well demonstrated by the literature that opioids are effective in controlling both acute and chronic pain of nociceptive and/or neuropathic origin. Switching type of opioid and/or administration routes (e.g., from oral to neuraxial) is also known to be an important factor in long-term treatment: appropriate conversion tables elucidating drug equipotence and different potency in base of administration route for the different opioids currently available have therefore been devised and validated in the clinical setting.
There have been several attempts to define guidelines for treatment protocols and even recent meta-analyses indicate that morphine should remain the gold standard. However, a general consensus is still lacking, as opioid management depends not only on the type and cause of pain, but also on the patient's history, the pain characteristics and genetic patterns. Which, if any, is the best opioid, in relation with previous characters, to start systemic treatment remains therefore debated. The different effects that different opioids have on spinal cord sensitization as a result of continuous peripheral nociceptive stimulus in long term administration have also been partially investigated.
Current pharmacogenetic publications analyze the pharmacokinetic behavior of opioids in short-term administration, but studies are still lacking on how the pharmacokinetics and analgesic effect vary after repeated administrations of opioids, especially through direct comparison with clinical response. Genetic studies showed differences in the results of opioid treatment related to the variability of the genes that have a role in the pharmacodynamic and pharmacokinetics of opioids. Regardless these studies, the literature has not yet investigated how quantitative and qualitative variability of gene products can influence the efficacy or the toxicity of a specific opioid treatment.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Oral extended-release morphine | Active comparator | Drug: Morphine |
| Oral extended-release oxycodone | Active comparator | Drug: Oxycodone |
| Transdermal fentanyl | Active comparator | Drug: Fentanyl |
| Transdermal buprenorphine | Active comparator | Drug: Buprenorphine |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Adult oncologic patients (>= 18 years old)
- Chronic peripheral neuropathic and/or nociceptive pain
- Written informed consent
Key exclusion criteria (8 listed)
- Pediatric patients
- Mental impaired patients
- Substance abuse disorder
- Opioid allergy
- History of opioids use or addiction
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MorphineAfter a titration phase with fast-release oral morphine, once the optimal dosage (no side effects and less than two rescue doses per day) is reached, an equipotent dose of oral sustained-release morphine will be randomly assigned to a patient. | Drug | Oral extended-release morphine |
| OxycodoneAfter a titration phase with fast-release oral morphine, once the optimal dosage (no side effects and less than two rescue doses per day) is reached, an equipotent dose of oral extended-release oxycodone will be randomly assigned to a patient. | Drug | Oral extended-release oxycodone |
| FentanylAfter a titration phase with fast-release oral morphine, once the optimal dosage (no side effects and less than two rescue doses per day) is reached, an equipotent dosage of transdermal fentanyl will be randomly assigned to a patient. | Drug | Transdermal fentanyl |
| BuprenorphineAfter a titration phase with fast-release oral morphine, once the optimal dosage (no side effects and less than two rescue doses per day) is reached, an equipotent dosage of transdermal buprenorphine will be randomly assigned to a patient. | Drug | Transdermal buprenorphine |
Primary outcome
To identify the drug with the best clinical-pharmacological safety-efficacy profile among the four opioids: oral extended-release morphine, oral extended-release oxycodone, transdermal fentanyl and transdermal buprenorphine.
Time frame: 15 days after randomization (Reduction of at least 40% of median daily pain, on a NRS)
We will define a treatment effective if it will produce a mean reduction of NRS values at least of 40% than basal values. Among all effective treatments, we will identify the best as the one that will have a reduction of NRS to a value of 4 or less in 90% of patients compared to the 70% of the others treatments. To evaluate pharmacological safety the plasma concentrations of the drugs and their metabolites will be measured. We will branch patients population in 3 groups to evaluate the correlation between clinical-pharmacological response and genetics (responder,partially and not responder)
1 secondary outcome
Pharmacokinetic of opioids and of their metabolites during long-term administration; correlation between specific genotypes and clinical response or the clinical/pharmacological susceptibility to side-effects on administration of a specific opioid.
Time frame: 6 months (each patient will be followed for 6 month after enrollment with clinical/pharmacological evaluations once a month and if inefficacy, tolerance or side effects)
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Jan 2014.
- Derived from this study: PubMed 24595069De Gregori S, Minella CE, De Gregori M, Tinelli C, Ranzani GN, Govoni S, Allegri M, Regazzi M. Clinical pharmacokinetics of morphine and its metabolites during morphine dose titration for chronic cancer pain. Ther Drug Monit. 2014 Jun;36(3):335-44. doi: 10.1097/FTD.0000000000000009.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Massimo Allegri, MD principal investigator
IRCCS Foundation Policlinico "San Matteo", Pavia, Italy
6 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Morphine, Oxycodone and Fentanyl in people with Chronic Pain, run by Fondazione IRCCS Policlinico San Matteo di Pavia at 6 sites in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: paused, as of the sponsor's last update on 9 Jan 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
To identify the drug with the best clinical-pharmacological safety-efficacy profile among the four opioids: oral extended-release morphine, oral extended-release oxycodone, transdermal fentanyl and transdermal buprenorphine. (time frame: 15 days after randomization (Reduction of at least 40% of median daily pain, on a NRS)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00916890, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Jan 2014.