The Role of Analgesic Adjustment Strategies in Achieving Analgesic Efficacy in Opioid-Tolerant Hospice Patients in China

Abstract

Diverse strategies of analgesic adjustment are often, respectively, used to sustain analgesic efficiency for opioid-tolerant patients with different refractory factors of pain. In order to select effective analgesic adjustment strategy for hospice patient without knowing explicit causes of diminishing analgesic efficiency, a retrospective data of 743 patients among 3760 hospice patients were analyzed. The efficacy and adverse effects were not significantly different among analgesic adjustment strategies at each adjustment. Opioid duration was not associated with clinical characteristics. For opioid-tolerant hospice patients, the analgesic adjustment strategy can be selected for individual patient. After repeated analgesic adjustments, opioid tapering may also occur.

Keywords

diverse strategies analgesic adjusted analgesic efficacy opioid tolerance hospice patients

Introduction

In all, 75% to 90% of patients with advanced cancer experience pain of various intensities,¹ rendering pain relief as major treatment objective in hospice care.² Although extended administration of opioid analgesics is required for moderate to severe chronic cancer pain, long-term acceptable pain control is not universally achievable.³ Repeated opioid adjustment was usually needed for hospice care to sustain analgesic efficiency.^3
–5 Many factors account for this diminishing efficacy. Besides the unmanageable adverse effects, psychological distress, age, gender, and race, other factors for refractory pain include malignant neuropathic pain, pharmacological tolerance, opioid-induced hyperalgesia, breakthrough pain, and disease progression.⁶

Currently, several analgesic adjustment strategies, including opioid dose escalation (ODE),^7
–9 adjuvant analgesics (AAs),^10

–14 opioid rotation (OR),^15
–17 and opioid tapering (OT),^8,18 could be chosen based on the distinguished refractory mechanism to block those pain. The most important mechanism of malignant neuropathic pain is central sensitization.¹⁹ Strategies such as ODE,⁷ AAs,^10
–12 and OR¹⁵ may elicit a satisfactory responsiveness. The pharmacological tolerance of opioids is characterized by analgesic tolerance related to a specific drug action and opioid–receptor desensitization.⁵ The ODE⁷ or a newer mixed μ-receptor agonists/δ-receptor antagonists²⁰ was the best strategy adopted to overcome it. The mechanism of opioid-induced hyperalgesia is opioid-induced sensitization that decreases nociceptive threshold.²¹ It can be improved using OR,¹⁶ AAs,¹³ N-methyl-D-aspartate (NMDA)-receptor antagonist,²² and even OT.¹⁸ Breakthrough pain is generally associated with chronic cancer pain and usually occurs spontaneously at the same site as background pain.²³ It is commonly managed using supplemental doses of immediate release opioids as rescue medication.⁹ Disease progression is associated with increasing pain intensity.²⁴ The dose response for analgesia shows no ceiling effect, and adequate pain relief can be achieved by ODE.^25,26

However, the factors responsible for diminishing analgesic efficacy show similar cellular mechanisms and usually present at the same time.⁸ In hospice home care, long-term use of opioids²⁷ is a common practice, but it is difficult to differentiate the causes for refractory pain. An imperative and practical question is how to select an appropriate analgesic adjustment strategy for hospice patients when their analgesic efficacy declines. The aim of this retrospective study was to evaluate the efficacy and safety of diverse analgesic adjustment strategies (including ODE, AAs, OR, and OT) among hospice patients with uncontrolled pain and to select an effective strategy for individual patient.

Methods

Procedure

This study was approved by Wuhan Hospice Center of China, National Hospice Service Program of Li Kashing Foundation. Consecutive patients admitted to service by hospice from February 2003 to March 2010 were reviewed retrospectively. We selected eligible patients using the following selection criteria.

Cancer pain treated with analgesics until the patient died according to the National Comprehensive Cancer Network (NCCN) Adult Cancer Pain Clinical Practice Guidelines in Oncology.²⁸ Oral and transdermal analgesics were the most common drugs of pain administered due to their minimally invasive nature.

Opioid-tolerant patients should have had an effective initial pain management. Opioid tolerance was defined as ≥60 mg oral morphine per day or an equianalgesic dose of another opioid for ≥1 week.²⁸

Diminishing analgesic efficacy self-reported by hospice patients and analgesic adjustment was necessitated at least once.

We classified groups according to the number of analgesic adjustments (1, 2, 3, and 4). Group 4 included patients who required ≥4 analgesic adjustments or required high opioid dosages (daily oral morphine equivalent values higher than 300 mg/d)²⁹ when the patient was admitted to hospice.

Diverse strategies of analgesic adjustment such as ODE, AAs, OR, and OT were used. The ODE as part of the regular schedule was calculated based upon the total opioid dosage from the previous 24 hours. Patients were still using their current analgesic (morphine, oxycodone, and fentanyl). The AAs consisted of the nonopioid analgesics (nonsteroidal anti-inflammatory drugs, acetaminophen, glucocorticoids, antidepressants, and anticonvulsants) combined with the same doses of current opioids of regular schedule. The OR switched from 1 opioid to another based on the opioid dose of regular schedule in the last 24 hours, according to the principles of opioid rotation (prescription, titration, and maintenance).²⁸ The OT involved the dose decrease in the regular schedule; the dose decrease is appropriately the amount of supplemental dose used at each time.

Measurements

For each hospice home care, a complete document of each patient and a patient self-report form about pain and prescription of analgesics were recorded and kept by the hospice staff. Complete demographic and clinical information was available for all patients, with particular attention paid to the following: pain type (nociceptive single pain or mixed pain, neuropathic single pain or mixed pain), opioid duration (defined from the day of an analgesic adjustment to the next), strategies of analgesic adjustment, analgesic efficacy, and side effects.

On each visit, pain and pain relief were evaluated before and after each analgesic adjustment by the Numerical Rating Scale (NRS) method.³⁰ The efficacy was categorized by investigators using a 4-point scale (unsatisfactory, moderate, good, and excellent), where unsatisfactory and moderate were regarded as inadequate and good and excellent as adequate.³¹

Statistics

The Statistical Package for Social Sciences (SPSS/Win, v.9.0) was used for statistical analysis, with P < .05 considered as statistically significant. A 1-way analysis of variance was used to detect the difference in opioid duration. Cross tables of descriptive statistics were selected to detect the differences in clinical characteristics, the rate of analgesic efficacy, and the incidence of side effects. Chi-square (χ²) tests were used to evaluate the significant differences. Binary logistic regression was employed to test the correlation between different variables (gender, age, pain type, opioid duration, and SAA) and analgesic efficacy.

Results

Demographic and Clinical Characteristics

A total of 3760 hospice patients with advanced cancer were reviewed, and 743 (20%) patients met the criteria for study inclusion (opioid tolerant and required analgesic adjustment)—728 cases needed analgesic adjustment repeatedly and 15 needed high dosages of opioid when they were admitted to hospice care. Patients included 421 men and 322 women with a median age of 55 years. Of those patients who entered the study, 91.9% had metastatic disease or relapse. The most common metastatic sites were bone and liver. The median duration of hospice care was 63 days (range: 7 -1537 days). There were 1448 person-times analgesic adjustments among the patients, and the mean time of analgesic adjustments was 1.75 ± 0.89. Table 1 lists the major demographic and clinical characteristics of each analgesic adjustment. The OT instead of adjuvant analgesics was only employed at adjustment 4. Opioid duration ranged from 30 days to 55 days, and they were not significantly different among diverse strategies at each analgesic adjustment.

Table 1.

Patient Demographic and Clinical Characteristics Stratified by Analgesic Adjustment.

	Adjustment 1	Adjustment 2	Adjustment 3	Adjustment ≥4^a
Cases, n	728	427	216	77
Gender, male/female, n	413/315	251/176	122/94	47/30
Age, year (range)	56 (10-91)	55 (13-90)	55 (13-89)	54 (17-81)
Pain type, n
SPNC	305	175	87	33
MPNC	56	43	17	18
SPNP	218	137	68	8
MPNP	149	72	38	18
SAA, n
ODE	472	298	140	32
AAs	143	70	47
OR	113	59	29	21
OT				24
Opioid duration, day (mean ± SD)
ODE	33.8 ± 35.2	36.9 ± 76.9	30.5 ± 34.7	48.6 ± 47.6
AAs	32.4 ± 32.2	31.8 ± 33.9	42.1 ± 54.3
OR	32.6 ± 27.2	55.1 ± 197.9	31.1 ± 32.9	39.0 ± 35.7
OT				30.0 ± 24.5
F	.120	1.041	1.564	1.608
P value^b	.887	.354	.212	.207

Abbreviations: SAA, strategies of analgesic adjustment; n, the cases of efficacy/the total cases of this group; AAs, adjuvant analgesia; ODE, opioid dose escalation; OR, opioid rotation; OT, opioid tapering; MPNC, mixed pain of nociceptive; MPNP, mixed pain with neuropathic; SPNC, single pain of nociceptive; SPNP, single pain of neuropathic.

^aRequired high opioid dosages (daily oral morphine equivalent values higher than 300 mg/d) which were needed when the patient was admitted to hospice.

^bThe P value is for the difference in opioid duration across adjustment strategies in each adjustment group.

Analgesic Efficacy of Diverse Strategies at Each Analgesic Adjustment

The efficacy of diverse strategies for achieving adequate analgesia after each analgesic adjustment was not significantly different, regardless of which analgesic adjustment was administered previously. The efficacy rate ranged from 69% to 78% among ODE, AAs, and OR following adjustment 1 (Table 2), from 64% to 100% following adjustment 2, and from 38% to 100% following adjustment 3, respectively. Although it was lower than those of other strategies (ODE and OR), the proportion of patients that achieved adequate analgesia in the OT group reached up to 54%, and there was no significant difference in any of the treatment groups (Table 3).

Table 2.

The Ratio of Analgesic Efficacy of Diverse Strategies From the First to the Third Analgesic Adjustment.

Adjustment 1			Adjustment 2			Adjustment 3
SAA	n	Ratio, %	SAA	n	Ratio, %	SAA	n	Ratio, %
ODE	366/472	77.5	ODE	150/196	76.5	ODE	47/64	73.4
						AAs	15/19	78.9
						OR	10/13	76.9
			AAs	34/48	70.8	ODE	10/14	71.4
						AAs	4/4	100
						OR	4/6	66.7
			OR	23/36	63.9	ODE	5/9	55.6
						AAs	2/3	66.7
						OR	3/3	100
AAs	101/143	70.6	ODE	51/61	83.6	ODE	13/18	72.2
						AAs	3/8	37.5
						OR	1/2	50.0
			AAs	11/16	68.8	ODE	6/6	100
						AAs	1/1	100
						OR	–	–
			OR	8/8	100	ODE	2/2	100
						AAs	–	–
						OR	2/2	100
OR	78/113	69.0	ODE	31/41	75.6	ODE	15/17	88.2
						AAs	6/10	60.0
						OR	2/2	100
			AAs	5/6	83.3	ODE	2/3	66.7
						AAs	–	–
						OR	1/1	100
			OR	11/15	73.3	ODE	7/7	100
						AAs	1/2	50.0
						OR	–	–

Abbreviations: AAs, adjuvant analgesia; ODE, opioid dose escalation; OR, opioid rotation.

Table 3.

The Ratio of Analgesic Efficacy in the Last Analgesic Adjustment.

	n	SAA			χ²	P Value
	n	ODE	OR	OT	χ²	P Value
Adjustment ≥4^a	77	75.0% (24/32)	57.1% (12/21)	54.2% (13/24)	3.098	.212

Abbreviations: ODE, opioid dose escalation; OR, opioid rotation; OT, opioid tapering;

SAA, strategies of analgesic adjustment; χ², chi-square.

^aRequired high opioid dosages (daily oral morphine equivalent values higher than 300 mg/d) that were needed when the patient was admitted to hospice.

Correlation Between Clinical Characteristics and Analgesic Efficacy

No significant difference was observed between analgesic efficacy and clinical characteristics, except for pain types in adjustment 1 and adjustment 3 (Table 4).

Table 4.

Correlations Between Factors and Analgesic Efficacy.

	Adjustment 1		Adjustment 2		Adjustment 3		Adjustment ≥4^a
	r	P	r	P	r	P	r	P
Gender	.000	.610	.028	.123	.064	.084	.000	.419
Age	.000	.313	.000	.467	.049	.109	.000	.263
Pain type	−.208	.000^b	.000	.409	.165	.003^b	.000	.806
OD	.000	.395	.000	.381	.000	.351	.000	.939
SAA	.000	.161	.000	.167	.000	.876	.000	.748

Abbreviations: OD, Opioid duration; r, regression; SAA, strategies of analgesic adjustment.

^a Required high opioid dosages (daily oral morphine equivalent values higher than 300 mg/d) which were needed when the patient was admitted to hospice.

^b P < .05.

Frequent Side Effects of Diverse Strategies of Analgesic Adjustment

The most common side effects reported by patients were constipation, nausea/vomiting, vertigo, urinary retention, and pruritus (Table 5). No significant difference between diverse strategies for each analgesic adjustment was observed.

Table 5.

Opioids Side Effects Among Diverse Strategies of Analgesic Adjustment, % (n).

		Constipation	Nausea/vomiting	Vertigo	Urinary retention	Pruritus
Adjustment 1
	ODE (n = 472)	90.5% (427)	21.8% (103)	12.5% (59)	5.1% (24)	3.0% (14)
	AAs (n = 143)	89.5% (128)	25.9% (37)	10.5% (15)	4.9% (7)	2.1% (3)
	OR (n = 113)	84.1% (95)	19.5% (22)	8.8% (10)	6.2% (7)	1.8% (2)
	P value	.142	.440	.501	.876	.706
Adjustment 2
	ODE (n = 298)	91.9% (274)	32.2% (96)	16.8% (50)	5.7% (17)	2.0% (6)
	AAs (n = 70)	87.1% (61)	28.6% (20)	15.7% (11)	12.9% (9)	4.3% (3)
	OR (n = 59)	89.8% (53)	30.5% (18)	13.6% (8)	5.1% (3)	5.1% (3)
	P value	.435	.830	.823	.086	.306
Adjustment 3
	ODE (n = 140)	91.4% (128)	38.6% (54)	25.0% (35)	6.4% (9)	2.9% (4)
	AAs (n = 47)	87.2% (41)	44.7% (21)	21.3% (10)	4.3% (2)	2.1% (1)
	OR (n = 29)	86.2% (25)	31.0% (9)	31.0% (9)	3.4% (1)	3.4% (1)
	P value	.562	.491	.634	.741	.939
Adjustment ≥4^a
	ODE (n = 32)	87.5% (28)	25.0% (8)	12.5% (4)	12.5% (4)	3.1% (1)
	OT (n = 24)	79.2% (19)	16.7% (4)	16.7% (4)	8.3% (2)	4.2% (1)
	OR (n = 21)	85.7% (18)	19.0% (4)	14.3% (3)	4.2% (1)	0.0% (0)
	P value	.684	.729	.907	.624	.661

Abbreviations: AAs, adjuvant analgesia; ODE, opioid dose escalation; OR, opioid rotation; OT, opioid tapering.

^a Required high opioid dosages (daily oral morphine equivalent values higher than 300 mg/d) that were needed when the patient was admitted to hospice.

Discussion

An adequate analgesic response is not universally achieved due to some factors that impact opioid responsiveness.^3,5,18 The strategy of ODE, AAs, OR, and OT, which can change the state of analgesia was obtained.^{5,7

–16,18,19} It is important that the causes of the reduced efficacy of opioids need to be distinguished, and then an appropriate strategy of analgesic adjustment is selected based on them. The ODE, as a logical approach, has been revisited to restore the analgesic effectiveness for opioid-tolerant patients with a worsening pain state.⁸ However, if refractory pain cannot be adequately managed by ODE, a strategy of limiting the escalation of the opioid dose would work.^8,18 The AAs, as a common strategy recommended by the NCCN guidelines,²⁸ have limitation because of the drug-related side effects.¹³ The OR has been used to treat uncontrolled pain or opioid-related adverse effect.¹⁵

Determining the causes of uncontrolled pain in a hospice setting is difficult.^8,18 Participants at hospice of China were the cases with low socioeconomic status, lingering pain, and no desire for any active cancer treatment except for self-delivered or easily administrated pain medication at home (hospice home care). With no desire for active antitumor treatment, both disease progression and pain intensity enhancement were unavoidable. With a long-term analgesic management, the ratio of opioid tolerance would be high. So, for hospice patients, the refractory elements might be more and more, which made it more difficult to discriminate the reasons of decline opioid efficacy because of the pattern of hospice home care. How can we select the appropriate strategy of analgesic adjustment for these hospice patients?

The differences between diverse analgesic adjustment strategies have seldom been compared without considering the causes of refractory pain. To the best of our knowledge, this was the first study examining opioid-tolerant patients in hospice care in China in order to assess the effect of diverse strategies for analgesia adjustment. Approximately 20% (743 of 3760) of the patients serviced by WuHan hospice of China required analgesic adjustment, and the analgesic efficacy rate was 50% to 80%. As shown in the current retrospective data, regardless of prevenient strategies, the analgesic efficacy of diverse strategies was similar. Previous studies have shown analogous clinical analgesic efficacies of diverse analgesic adjustment.^{9,10,12,15,18} Especially, a total adequate analgesia range of 60% to 70% on opioid rotation achieved in our study were similar to the results obtained among outpatients reported by Reddy et al.³² So, different strategies could be adopted repeatedly based on the clinical analgesic experience to antagonize the numerous factors of poor opioid responsiveness.

In the current study, the rate of analgesic efficacy in the OT group was 54% among those patients selected and was similar to other strategies. Appropriate OT could be recommended to the patients who needed repeated adjustment of analgesia or higher opioid dosages to manage severe pain.

Unlike the previous results,⁵ the efficacy of diverse strategies of analgesic adjustment we currently demonstrate was not associated with age or gender. These associations were in agreement with another study on our hospice patients, and the potential reasons might be that patients who received service from our hospice were patients with terminal cancer, and the survival time was limited.⁴ Previous studies have also shown that the type of pain experienced by the patient may influence opioid responsiveness, especially for neuropathic pain.^5,10 The hospice setting might have contributed to the lack of pain-type assessment during hospice care. Comprehensive pain assessment should continue to be emphasized when opioid responsiveness is in decline.

The long-term use of opioids might be associated with opioid tolerance.¹⁸ For individual patient and the different prevenient strategies managed, the relationship between opioid duration and opioid tolerance was unclear. We found that opioid duration in each analgesic adjustment was 30 to 50 days, and there was no difference in each analgesic adjustment, respectively. This might help to distinguish the events of opioid tolerance and lack of analgesic dosage at each analgesic adjustment and to select right analgesic prescription for patients who did not achieve pain relief after analgesic adjustment.

A recent review showed that almost all patients (96%) experienced opioid-related side effects, and the majority (79%) of patients with chronic pain were recorded as having 2 or more side effects.³³ In the current study, the major side effects were constipation, nausea/vomiting, vertigo, urinary retention, and pruritus. The rates of side effects were similar regardless of the analgesic strategy employed. The incidence of each side effect was higher than the previous study.³³ The reasons for the higher rate of side effects may be due to comorbidities and concurrent medications.

As a retrospective study, our data had several limitations. Some future prospective studies about opioid adjustment for outpatients were needed to develop effective strategies after more follow-up visits and identify the predictors of a successful strategy.³² We were only enthusiastic about the effective diverse strategies of opioid adjustment because of the difficulties in identifying the changes of pain mechanism via regular telephone calls. Many other analgesic adjustment strategies have been introduced to improve opioid responsiveness.¹³ Some of them were limited to safe use of long-term opioid therapy in hospice care because of parenteral administration and the high incidence of severe adverse effects. For example, ketamine, a representative medication of NMDA antagonists, was used in very low doses for refractory pain.²² However, the poor effect of oral ketamine on pain scores of cancer pain³⁴ and significant side effects³⁵ made it difficult to use conveniently and safely. Moreover, the use of opioids as monotherapy with the least invasive method of administration was common.²⁸ Furthermore, our hospice service as a benevolent program had to use the existing medications and unambiguous analgesic strategy to manage cancer pain with ease, considering safety.

Conclusions

This is the first study examining hospice patients in mainland China which demonstrated the similar analgesic efficacy of adjusted strategies including ODE, AAs, OR, and OT. Any difference was not significant. By assessing the result, the hospice staff can offer another individualized adjusted strategy for the patient who needs sustained analgesic efficacy. These findings have provided reliable information for improving hospice care for this special group of people.

Footnotes

Acknowledgments

The authors are very grateful to Prof Yan Li for fruitful discussion and editorial improvement of this manuscript

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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