Hydromorphone for cancer pain

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To determine the analgesic efficacy of hydromorphone in relieving cancer pain, as well as the incidence and severity of any adverse effects.

Background

This new protocol updates a previous review, 'Hydromorphone for acute and chronic pain', published in The Cochrane Library (Issue 1, 2002). This review will only focus on cancer pain.

Description of the condition

Pain is defined as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage" (IASP 2011).

Cancer pain is an important and distressing symptom of the disease, which tends to increase in frequency and intensity as the cancer advances. For cancer patients, pain can arise from the progression of the cancer itself as well as from treatments designed to alleviate the condition such as radiotherapy, chemotherapy and surgery. Cancer-related pain can be classified as acute or chronic, though is sometimes thought to be an ongoing acute pain. Acute pain is defined as having "a temporal pattern of onset... generally associated with subjective and objective physical signs," whereas chronic pain is more continuous, lasting three months or longer.

Increasingly, the treatment of cancer-related pain has become a major challenge within the healthcare sector. A previous systematic review has indicated the prevalence of pain to be more than 50% in all cancer types (Van den Beuken-van Everdingen 2007). For patients with advanced cancer, the prevalence of pain can be as high as 90% (Laird 2008). It has been estimated that 30% to 50% of cancer patients categorise their pain as moderate to severe and that between 75% to 90% of cancer sufferers experience pain, which has a major impact on their daily life (Portenoy 1999). Epidemiological studies suggest that approximately 15% of patients who experience pain fail to experience acceptable pain relief with conventional management (Running 2011; Yakovlev 2008). Uncontrolled pain can lead to physical and psychological distress and can, consequently, have a drastic effect on patients' quality of life.

Description of the intervention

The options available for managing cancer-related pain include pharmacological treatments (e.g. opioid analgesics), psychological therapy (e.g. cognitive behavioural therapy) and alternative treatments (e.g. acupuncture or massage). Opioid pharmacotherapies (such as morphine, oxycodone, fentanyl, hydromorphone and methadone) have been put forward as the most effective of these therapies (Portenoy 2011).

The World Health Organization (WHO) has recommended oral morphine as the first choice for the management of moderate to severe cancer-related pain (WHO 1986). This has been stated to be largely due to its cost and availability rather than proven superiority (Caraceni 2012), with a previous review suggesting that a significant proportion of patients do not achieve sufficient pain relief by taking morphine due to unmanageable adverse effects, including nausea, delirium or myoclonus (Murray 2005). However, evidence from a recent Cochrane review on oral morphine for cancer pain suggests that only around 5% stopped taking morphine due to lack of pain relief or unacceptable adverse effects (Wiffen 2013). Morphine may also be associated with toxicity in patients with renal impairment (King 2011).

Hydromorphone (also know as dihydromorphinone) is a semi-synthetic derivative of morphine. It is marketed in various countries under various brand names. Since its clinical introduction in 1926, it has been used as an alternative opioid analgesic to morphine, as it has a similar chemical structure but is more soluble (Urquhart 1988) and potent (Twycross 1994). High solubility is beneficial for opioid-resistant patients who require higher doses (Portenoy 2011) and OROS® hydromorphone extended-release is five times as potent as morphine, and has 8.5 times the equianalgesic effect when administered intravenously (Binsfeld 2010; Sarhill 2001). This also allows a smaller dose of hydromorphone to be used for an equianalgesic effect. Hydromorphone is administered through oral, intravenous, subcutaneous, epidural, intrathecal and other routes (Murray 2005).

How the intervention might work

Like morphine, hydromorphone is primarily an agonist at μ receptors, displaying weak affinity for κ-opioid receptors. μ receptors mediate the pain-relieving properties but they can also result in adverse effects like nausea, constipation and respiratory depression (Murray 2005). One systematic review has shown that hydromorphone has similar analgesic and side effects to morphine (Miller 1999), while a more recent review concludes that no study can clearly demonstrate whether hydromorphone is better than oral morphine (Pigni 2011).

Hydromorphone, in common with other opioid analgesics, has the potential to produce adverse effects that include respiratory depression, nausea, vomiting, constipation and itching. Tolerance may develop during chronic opioid therapy such that larger doses may be required to sustain the analgesic effect. In addition, patients can be at risk of physiological dependence and experience opioid withdrawal syndrome upon sudden cessation of the opioid or administration of an antagonist. Side effects from opioid analgesics are not always seen as adverse effects, however. When used for the relief of pain in malignant disease, the actions of relieving anxiety, producing drowsiness and allowing sleep may be welcome (Grahame-Smith 2002).

Why it is important to do this review

This is one of a suite of reviews looking at analgesics for cancer pain. Although WHO recommends oral morphine as first-line analgesia for cancer-related pain, the use of hydromorphone remains a consideration in some circumstances (Wiffen 2013). Previous systematic reviews have compared the efficacy and side effects of hydromorphone with other medications, but the inconsistency of their conclusions and the low quality of the studies that were included suggest that further research is needed. This review will update the evidence by evaluating the effectiveness of hydromorphone for cancer-related pain and examining the incidence and severity of its side effects.

Objectives

To determine the analgesic efficacy of hydromorphone in relieving cancer pain, as well as the incidence and severity of any adverse effects.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs), parallel or cross-over and of any duration, which focus on hydromorphone for the treatment of cancer pain and that assess pain as an outcome measure will be eligible for inclusion in this review. We will exclude studies that do not state that participants were allocated at random.

Types of participants

We will include studies of both adults and children with moderate to severe cancer pain (as defined in each study) who have been clinically assessed as requiring treatment with opioid analgesia.

Types of interventions

We will include studies in which hydromorphone (any dose and form of administration) is the active intervention. Comparison conditions may be placebo, an alternative opioid or another active control.

Types of outcome measures

We will assess participant-reported pain intensity and pain relief through the use of validated pain scales, including visual analogue scales (VAS) and categorical scales.

Primary outcomes
  • Participant-reported pain intensity levels measured using a validated visual analogue or categorical pain scale. We are particularly interested in, but not limited to, numbers of participants who achieve 'no worse than mild pain' (Moore 2013). This has been considered no or mild pain, 3/10 on a numerical rating scale, or 30/100 mm on a visual analogue scale (Wiffen 2013). We will not consider physician-, nurse- or carer-reported measures of pain.

  • Participant-reported pain relief measured using a validated scale.

Secondary outcomes
  • Adverse effects, e.g. drowsiness/sedation, nausea, constipation (incidence and severity, as defined and measured in each study).

  • Improvement in participants' quality of life measured using the EuroQol EQ-5D, the World Health Organization Quality of Life Assessment or a similar validated quality of life instrument.

  • Leaving the study early or discontinuation of treatment for any reason.

  • Death.

Search methods for identification of studies

Electronic searches

To identify potentially relevant studies to be assessed for inclusion in this review, we will search the following databases. We will use the search strategy reported in Appendix 1 for searching MEDLINE via Ovid SP and will adapt this for each of the other databases.

  • Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, latest issue).

  • MEDLINE (1946 to present).

  • EMBASE (1974 to present).

Searching other resources

In an attempt to identify any relevant published or unpublished reports not found in the electronic searches, we will manually check the references of each included paper. We will contact the authors of each included paper and of publications which are only available in abstract format. We will also contact representatives from the pharmaceutical companies marketing hydromorphone to ask for any relevant published or unpublished studies, or missing data.

There will be no limitation on publication date or on language and we will assess non-English papers and translate as necessary. We will also search for ongoing trials in the metaRegister of controlled trials (mRCT) (www.controlled-trials.com/mrct), clinicaltrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (http://apps.who.int/trialsearch/).

Data collection and analysis

Selection of studies

Two review authors (YJB and BJH) will assess the titles and abstracts of all studies identified by the searches and will independently consider the full records of all potentially relevant studies for inclusion by applying the selection criteria outlined in the Criteria for considering studies for this review section. We will resolve disagreements by discussion. The inclusion criteria are not restricted by date or language. To promote transparency of the search and systematic review process, we will produce a PRISMA flow diagram, as per the PRISMA statement (Moher 2009).

Data extraction and management

We will extract data using the Cochrane Pain, Palliative and Supportive Care Group's recommended data extraction form and will record baseline data on participants, together with details of interventions, outcomes and results relevant to our review. Where we identify a study that includes a subset of participants who receive hydromorphone, we will extract data from this group. We will resolve any disputes by discussion.

Assessment of risk of bias in included studies

Two authors (YJB and BJH) will independently assess the methodological quality of each included study using the 'Risk of bias' assessment method outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). This will include the following risk of bias domains: allocation and randomisation methods; blinding and methods of maintaining; selective reporting of outcome measures; incomplete outcome data and 'other' sources of bias, for example, sources of funding. We will rate the aforementioned domains as either 'low risk', 'high risk' or 'unclear risk' of bias. We will complete a 'Risk of bias' table for each included study. We will resolve any disagreements between the assessors by discussion. Small studies have been shown to overestimate treatment effects, probably due to methodological weaknesses (Moore 2012; Nüesch 2010); therefore, we will consider studies to be at low risk of bias if they have 200 or more participants, at unclear risk if they have between 50 and 200 participants, and at high risk if they have fewer than 50 participants (Wiffen 2013).

Measures of treatment effect

For dichotomous outcomes, we will calculate the risk ratio (RR) and the corresponding 95% confidence interval (CI) and P value. For continuous outcomes, we will calculate the mean difference (MD) and its corresponding 95% CI when means and standard deviations are available. If such information is unavailable, we will use the methods described in Chapter 16 of the Cochrane Handbook for Systematic Reviews of Interventions to calculate standardised mean differences (SMD) from, for example, F ratios, t-values, Chi2 values and correlation coefficients (Higgins 2011). In cases where continuous measures are used to assess the same outcomes using different scales, we will pool these data using Hedges' g to estimate the SMD. When effect sizes cannot be pooled, we will report study-level effects narratively. We will calculate numbers needed to treat (NNT) for both beneficial and detrimental events for statistically significant outcomes.

Unit of analysis issues

We will only include studies that randomise the individual patient.

Dealing with missing data

We will assess missing data in the included studies. We will investigate and report the reasons, numbers and characteristics of those dropping out of each included study. Where studies are identified as having missing data, we will initially attempt to contact the study authors to obtain this information. For dichotomous outcomes, we will perform an intention-to-treat (ITT) analysis. If there is missing participant information, we will record this and comment in the individual study's 'Risk of bias' table. We will assign participants with missing data to a 'zero improvement' category, and we will perform a sensitivity analysis comparing the resulting effect sizes with those obtained using completer-only data. For continuous outcomes, we will use baseline observation carried forward (BOCF), where rating scales have been employed. Where data are missing from substantial numbers of participants (> 10%), we will rate the study as a high risk of bias.

Assessment of heterogeneity

We will assess for heterogeneity among primary outcome studies using the I2 statistic along with its corresponding P and Chi2 value (Higgins 2011), and will discuss any observed heterogeneity and its magnitude. If heterogeneity is identified, we will investigate possible sources using subgroup analyses and sensitivity analyses.

Data synthesis

We will enter all extracted data into Review Manager software for meta-analysis, where possible (RevMan 5.2). In order to take into account differences between studies, we will synthesise data using a random-effects model. We will also use a fixed-effect model in a sensitivity analysis in order to investigate any differences in the estimate of effect. We will meta-analyse data where possible; however, if this is not feasible, we will narratively summarise the data in our main results, discussion and relevant tables.

Subgroup analysis and investigation of heterogeneity

If data are available, we plan to carry out the following subgroup analyses:

  • for method of administration (long-acting and short-acting);

  • for single dose versus multiple dose;

  • by type of cancer;

  • by age.

Sensitivity analysis

If sufficient data are available, we will examine the robustness of the meta-analyses by conducting sensitivity analyses. For this, we plan to exclude studies that are rated as 'high risk of bias' across any one of the risk of bias domains in order to assess any differences in the estimate of treatment effect. We further plan to conduct a sensitivity analysis for high levels of attrition (> 10%) in individual studies, comparing completer-only data with our assumptions of ITT, and to assess any differences when synthesising data using a fixed-effect rather than a random-effects model.

Acknowledgements

The authors would like to thank Mr Farhad Shokraneh for his contribution to the development of the search strategy.

Appendices

Appendix 1. Appendix 1. MEDLINE search strategy via Ovid SP

1. Hydromorphone/

2. Hydromorphon*.it,ab.

3. Dihydromorphinone.ti,ab.

4. Hydromorphon.ti,ab.

5. Palladone.ti,ab.

6. Laudacon.ti,ab.

7. Dilaudid.ti,ab.

8. or/1-7

9. NEOPLASMS*:ME

10. neoplasm*

11. malignan*

12. tumour* OR tumor*

13. cancer*

14. carcinoma*

15. or/9-14

16. exp Pain/

17. Pain Measurement/

18. Pain Threshold/

19. Pain* or nocicept* or nocicept* or neuropath*.ti.ab.

20. or/16-19

21. randomized controlled trial.pt.

22. controlled clinical trial.pt.

23. randomized.ti,ab. or randomised.ti,ab.

24. placebo.ti,ab.

25. drug therapy.fs.

26. randomly.ab.

27. trial.ab.

28. groups.ab.

29. or/21-28

30. (animals not (humans and animals)).sh.

31. 29 not 30

32. 8 and 15 and 20 and 31

Contributions of authors

All authors contributed equally to the development of this protocol.

Declarations of interest

We are not aware of any existing conflict of interest.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Science and Technology Department, China.

    The current work was partially supported by the National Special Issue Research Program of Science and Technology Department of China (no. 2010ZX09102-216)

  • National Natural Science Foundation Project, China.

    Project No. 81273718 and No. 81302961

Notes

This protocol and full review will replace the original review, 'Hydromorphone for acute and chronic pain', as the original author team were unavailable to complete the update (Quigley 2013). The new review will focus on cancer pain only.

Ancillary