Long-term low-dose transdermal buprenorphine therapy for chronic noncancer pain
-
Petter C Borchgrevink
This issue of the Scandinavian Journal of Pain presents the first controlled opioid trial for chronic noncancer pain with a study-duration lasting more than a few months [1]. This double blind placebo-controlled study compares low dose transdermal buprenorphine (LD-TD-BUP) with placebo patches for osteoarthritis (OA) pain. The “world-record” earlier of randomised controlled trials for opioids to patients with chronic non-malignant pain was a four months double blind comparison of tramadol plus paracetamol with placebo for chronic low back pain [2,3]. Before that, published double blind, placebo-controlled potent-opioid studies lasted only from 3 days up to 2 months [3,4].
Although transdermal buprenorphine in doses of 35 and 70 μg/h, being suitable for cancer pain, has been on the market since 2001, the recent introduction of LD-TD-BUP in 5, 10, and 20 μg/h patches for seven days in many ways represents a new drug concept [5,6]. It is the first preparation designed specifically for chronic non-cancer pain patients with the intention of stabilizing their opioid consumption [5,6]. According to the producer LD-TD-BUP delivers buprenorphine at a stable rate after a plateau is reached 3 days after application of the first patch of the chosen dose. Thus it is not suitable for acute and unstable pain, and due to its low dose, it should not be used for cancer related pain.
So what did this six months study reveal about treatment of opioids for chronic non-malignant pain? It confirms with a placebo-controlled trial what we have expected from clinical experience, namely that opioid treatment for such relatively moderate nociceptive pain is more effective than placebo. The study showed that a low median dose of 10 μg LD-TD-BUP per hour in opioid naïve patients does relieve daytime movement-related pain in patients with moderate to severe OA of the weight-bearing hip or knee-joint and that the patients experienced a significantly globally improved change in their health status during the six months of LD-TD-BUP patch treatment [1].
The present study gives an important, although limited contribution to solve one of the issues considered to be the most controversial in the field of pain medicine, namely to which extent opioids should be used for chronic non-malignant pain to patients with long life expectancies. Whether LD-TD-BUP has an effect on more severe chronic pain is, however, doubtful. As indicated in the extended abstract by Breivik et al. [1], LD-TD-BUP is not effective against more severe chronic nociceptive pain, since eight patients in each group with very severe degree of OA had to be excluded in a subgroup analyses to reach a significant improvement compared to placebo for the primary outcomes. Also, a few withdrew from the study a few days before completing all six months of double blind treatment.
It is also doubtful if LD-TD-BUP is effective if patients have used other opioids before, particularly of the short acting type. As the authors comment, LD-TD-BUP might have less analgesic effect if the patients have been using opioids like codeine for prolonged periods before entering the study. In a previous study from the Norwegian Prescription Database, almost all patients who were prescribed LD-TD-BUP used short acting opioids, mostly codeine, before [7]. Only six percent of all new users did not utilize short acting opioids before the start of LD-TD-BUP. The study by Skurtveit et al. [7] also showed that more than half of those who formerly used short acting opioids continued to use other opioids and benzodiazepines after being prescribed LD-TD-BUP. An abstract presented in this issue of the Scandinavian Journal of Pain reports that 82% of long-term LD-TD-BUP users with a previous opioid history, co-medicated with other opioids and/or benzodiazepines [8].
The two cited studies from the Norwegian Prescription Database also show that most patients starting with LD-TD-BUP only received one prescription and did not continue the treatment meant for long-term use [7,8]. During the three years 2005–2007 as many as 0.4% of Norwegians had tried LD-TD-BUP, but only 21% of these became long-term users [8]. Both these studies indicate that most patients with chronic pain, previously on codeine-containing analgesics, who have been prescribed LD-TD-BUP, do not find that this patch treatment is effective. They also document that most long-term users combine LD-TD-BUP with short acting opioids and/or benzodiazepines. Thus the introduction of LD-TD-BUP has so far not met the expectations that it would stabilize long-term use of opioids without co-medication with other potentially addictive drugs.
Thus, the three cited studies [1,7,8] all indicate that LD-TD-BUP should be used in a selected group of patients who are opioid naïve and have both relatively moderate and stable chronic pain. Some OA patients with pain clearly belong to this group. A more heterogenic group could be opioid-naïve, e.g., elderly patients who develop chronic pain. The elderly patients with chronic pain should not be treated with NSAIDs. Beside paracetamol, a low and stable dose of opioid is the only alternative in many cases. Older persons are particularly sensitive to the side effects of opioids, as of most co-analgesics such as tricyclic antidepressants and gabapentionoids [1]. Therefore, also LD-TD-BUP treatment must be closely monitored for adverse effects.
To perform a long-term double blind opioid study that is clinically relevant for chronic pain states is challenging. It has been predicted in an editorial that we would never see appropriate length double blind opioid trials because the pharmaceutical companies marketing opioids are not interested and the national medicines agencies do not have the resources or motivation to do such studies [9]. However, the author of that editorial, Harald Breivik, now, seven years later together with his co-workers and sponsor, disproved that prophesy. They have documented that it is possible to perform a high-quality randomized control trial with placebo control during a time period that is sufficiently long to give clinically meaningful data on effects as well as safety and tolerability of long-term opioid treatment.
A reason that the study could be performed for so long as six month was that the opioids were released with a low and stable dose making it possible without unblinding patients and observers with outspoken side effects. Other reasons are that the patients were opioid naïve at the beginning of the study and that their chronic pain state was not too severe. Perhaps the author of the cited editorial [9] after all was right when he predicted that it will be difficult to perform long lasting randomised control trials of opioids in the future and that the present study in this issue of Scandinavian Journal of Pain represents an exception [1]. Since we still need much more scientific background to treat patients with chronic pain with opioids over years, it is important to perform more studies using other methods than RCT, like longitudinal epidemiological studies, long-term open clinical trials, and qualitative studies.
DOI of refers to article: 10.1016/j.sjpain.2010.05.035.
References
[1] Breivik H, Ljosaa TM, Stengaard-Pedersen K, Bliddal H, Persson J, Aro H, Villumsen J, Tvinnemose D. A 6-months, randomised, placebo-controlled evaluation of efficacy and tolerability of a 7-day buprenorphine transdermal patch in osteoarthritis patients naïve to potent-opioids. Scand J Pain 2010;1:122-41.Suche in Google Scholar
[2] Peloso PM, Fortin L, Beaulieu A, Kamin M, Rosenthal N, Protocol TRP-CAN-1 Study Group. Analgesic efficacy and safety of tramadol/acetaminophen combination tablets (Ultracet) in treatment of chronic low back pain: a multicenter, outpatient, randomized, double blind, placebo controlled trial. J Rheumatol 2004;31:2454-63.Suche in Google Scholar
[3] Noble M, Treadwell JR, Tregear SJ, Coates VH, Wiffen PJ, Akafomo C, Schoelles KM. Long-term opioid management for chronic noncancer pain. Cochrane Database Syst Rev 2010;(1), doi:10.1002/14651858. CD006605.pub2.Suche in Google Scholar
[4] Kalso E, Edwards JE, Moore A, McQuay HJ. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. Pain 2004;112:372-80.Suche in Google Scholar
[5] Johnson RE, Fudala PJ, Payne R. Buprenorphine: considerations for pain management. J Pain Symptom Manage 2005;29:297-326.Suche in Google Scholar
[6] Vadivelu N, Hines RL. Buprenorphine: a unique opioid with broad clinical applications. J Opioid Manag 2007;3:49-58.Suche in Google Scholar
[7] Skurtveit S, Furu K, Kaasa S, Borchgrevink PC. Introduction of low dose transdermal buprenorphine - did it influence use of potentially addictive drugs in chronic non-malignant pain patients? Eur J Pain 2009;13:949-53.Suche in Google Scholar
[8] Nordbø A, Skurtveit S, Borchgrevink PC, Kaasa S, Fredheim O. Is transdermal buprenorphine for chronic non-malignant pain used long term without co-medication with other potentially addictive drugs? Abstract at congress of the new Scandinavian Association for the Study of Pain. Scand J Pain 2010;1, xx-xx.Suche in Google Scholar
[9] Breivik H. Appropriate and responsible treatment of cncp with opioids. Eur J Pain 2003;7:379-80.Suche in Google Scholar
© 2010 Scandinavian Association for the Study of Pain
Artikel in diesem Heft
- Editorial comment
- Functional brain imaging of acute postoperative pain
- Clinical pain research
- Brain activation due to postoperative pain from the right hand measured with regional cerebral blood flow using positron emission tomography
- Editorial comment
- Long-term low-dose transdermal buprenorphine therapy for chronic noncancer pain
- Original experimental
- A 6-months, randomised, placebo-controlled evaluation of efficacy and tolerability of a low-dose 7-day buprenorphine transdermal patch in osteoarthritis patients naïve to potent opioids
- Editorial comment
- Repeated nociceptive stimulation for detecting drug effects
- Original experimental
- The effects of gabapentin in human experimental pain models
- Editorial comment
- Whether the weather influences pain: High prevalence of chronic pain in Iceland and Norway: Common genes? Or lack of sunshine and vitamin D?
- Observational studies
- A population based study of the prevalence of pain in Iceland
- Editorial comment
- Swedish nurses are prone to chronic shoulder and back pain because of miserable working conditions and poor leadership?
- Observational studies
- Predicting of pain, disability, and sick leave regarding a non-clinical sample among Swedish nurses
- Abstracts
- Trigeminal neuralgia or odontogenic pain
- Abstracts
- What’s wrong with animal models of pain?
- Abstracts
- Immunotherapy for neuroblastoma elicits a complement dependent whole body allodynia
- Abstracts
- Pain mechanisms in animal models of rheumatoid arthritis
- Abstracts
- Translating basic research to pharmacological treatment of neuropathic pain
- Abstracts
- Free Poster Presentations: Forearm heat pain does not inhibit electrically induced tibialis anterior muscle pain
- Abstracts
- Offset analgesia evoked by non-contact thermal stimulator
- Abstracts
- Inhibition of FAAH reverses spinal LTP
- Abstracts
- Hyperexcitable C-nociceptors in human paroxysmal pain
- Abstracts
- Pain sensitivity and experimentally induced sensitization in red haired women
- Abstracts
- How are opioids used in Norway? Persistent use, utilization of depot formulation and age profile in non-palliation patients
- Abstracts
- To which extent does incident and persistent use of weak opioids predict problematic opioid use?
- Abstracts
- Is transdermal buprenorphine for chronic non-malignant pain used long term without co-medication with other potentially addictive drugs?
- Abstracts
- Prostaglandin E2 production in synovial tissue and acute postoperative pain after knee arthroscopy
- Abstracts
- Girl presenting with oesophageal spasm pain after fundoplication
- Abstracts
- Epidemiology of persistent postoperative pain: Association of persistent pain and sensory abnormalities
- Abstracts
- Cost–benefit of a 13-week multidiciplinary rehabilitation course for chronic non-malignant pain patients
- Abstracts
- A novel and effective treatment modality for medically unexplained pain
- Abstracts
- Somatocognitive therapy in the management of chronic gynaecological pain. A review of current approach and historical background
- Abstract
- The Manual Intervention Trial (MINT)—The effect of various combinations of naprapathic manual therapy. The study protocol of a randomized controlled trial
- Abstracts
- The experience of chronic pain, loss and grief
- Abstracts
- Effect of buprenorphine and fentanyl in experimental induced superficial, deep and hyperalgesic pain
- Abstract
- Pretreatment with opioids enhances afferent induced long-term potentiation in the rat dorsal horn
- Abstracts
- Pigs in pain—Porcine behavioural responses towards mechanical nociceptive stimulation directed at the hind legs
- Abstracts
- A human experimental bone pain model
Artikel in diesem Heft
- Editorial comment
- Functional brain imaging of acute postoperative pain
- Clinical pain research
- Brain activation due to postoperative pain from the right hand measured with regional cerebral blood flow using positron emission tomography
- Editorial comment
- Long-term low-dose transdermal buprenorphine therapy for chronic noncancer pain
- Original experimental
- A 6-months, randomised, placebo-controlled evaluation of efficacy and tolerability of a low-dose 7-day buprenorphine transdermal patch in osteoarthritis patients naïve to potent opioids
- Editorial comment
- Repeated nociceptive stimulation for detecting drug effects
- Original experimental
- The effects of gabapentin in human experimental pain models
- Editorial comment
- Whether the weather influences pain: High prevalence of chronic pain in Iceland and Norway: Common genes? Or lack of sunshine and vitamin D?
- Observational studies
- A population based study of the prevalence of pain in Iceland
- Editorial comment
- Swedish nurses are prone to chronic shoulder and back pain because of miserable working conditions and poor leadership?
- Observational studies
- Predicting of pain, disability, and sick leave regarding a non-clinical sample among Swedish nurses
- Abstracts
- Trigeminal neuralgia or odontogenic pain
- Abstracts
- What’s wrong with animal models of pain?
- Abstracts
- Immunotherapy for neuroblastoma elicits a complement dependent whole body allodynia
- Abstracts
- Pain mechanisms in animal models of rheumatoid arthritis
- Abstracts
- Translating basic research to pharmacological treatment of neuropathic pain
- Abstracts
- Free Poster Presentations: Forearm heat pain does not inhibit electrically induced tibialis anterior muscle pain
- Abstracts
- Offset analgesia evoked by non-contact thermal stimulator
- Abstracts
- Inhibition of FAAH reverses spinal LTP
- Abstracts
- Hyperexcitable C-nociceptors in human paroxysmal pain
- Abstracts
- Pain sensitivity and experimentally induced sensitization in red haired women
- Abstracts
- How are opioids used in Norway? Persistent use, utilization of depot formulation and age profile in non-palliation patients
- Abstracts
- To which extent does incident and persistent use of weak opioids predict problematic opioid use?
- Abstracts
- Is transdermal buprenorphine for chronic non-malignant pain used long term without co-medication with other potentially addictive drugs?
- Abstracts
- Prostaglandin E2 production in synovial tissue and acute postoperative pain after knee arthroscopy
- Abstracts
- Girl presenting with oesophageal spasm pain after fundoplication
- Abstracts
- Epidemiology of persistent postoperative pain: Association of persistent pain and sensory abnormalities
- Abstracts
- Cost–benefit of a 13-week multidiciplinary rehabilitation course for chronic non-malignant pain patients
- Abstracts
- A novel and effective treatment modality for medically unexplained pain
- Abstracts
- Somatocognitive therapy in the management of chronic gynaecological pain. A review of current approach and historical background
- Abstract
- The Manual Intervention Trial (MINT)—The effect of various combinations of naprapathic manual therapy. The study protocol of a randomized controlled trial
- Abstracts
- The experience of chronic pain, loss and grief
- Abstracts
- Effect of buprenorphine and fentanyl in experimental induced superficial, deep and hyperalgesic pain
- Abstract
- Pretreatment with opioids enhances afferent induced long-term potentiation in the rat dorsal horn
- Abstracts
- Pigs in pain—Porcine behavioural responses towards mechanical nociceptive stimulation directed at the hind legs
- Abstracts
- A human experimental bone pain model
